Special Issue "Cell Death and Cancer"

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A special issue of Cancers (ISSN 2072-6694).

Deadline for manuscript submissions: closed (30 December 2010)

Special Issue Editor

Guest Editor
Prof. Dr. Afshin Samali

Director of Apoptosis Research Centre, School of Natural Sciences, National University of Ireland - Galway, University Road, Galway, Ireland
Website | E-Mail
Fax: +353 91 494596
Interests: apoptosis; cell death; autophagy; TRAIL; heat shock proteins; Endoplasmic Reticulum stress; hypoxia

Special Issue Information

Dear Colleagues,

Cell death is involved in a variety of biological processes including morphogenesis, maintaining tissue homeostasis and elimination of harmful cells. Deregulation of proliferation, together with a reduction in cell death, is both necessary and sufficient for tumor development, progression, and resistance to therapy. The mechanisms of cell death and cell survival are complex and involve not only apoptosis and necrosis, but also their cross-talk with other programmed intracellular processes such as autophagy. In addition, the tumor microenvironment has a great impact on cell death, cell signaling, tumor metabolism, cell survival, and therapeutic responsiveness. The central focus of the special issue on “Cell Death and Cancer” is cell death regulation and how to exploit it for therapeutic gain. The main topics will include, but are not limited to, the role of cell death (e.g., apoptosis and necrosis) and cell survival pathways (e.g., autophagy) in tumorigenesis; targeting autophagy and cell death pathways for tumor eradication; death receptor and mitochondria-mediated apoptosis; stress-activated and survival-related protein kinases (e.g., p38, JNK, AKT, etc.) and their role in cell death; novel strategies to target anti-apoptotic proteins (SMAC mimetics, BH3 mimetics etc.).

Thank you for your collaboration.

Prof. Dr. Afshin Samali
Guest Editor

Keywords

  • apoptosis
  • autophagy
  • Bcl-2 family
  • caspases
  • cell death
  • cell survival
  • death receptors
  • mitochondria
  • oncogenes
  • tumor suppressor genes

Published Papers (25 papers)

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Research

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Open AccessArticle The Proteasome Inhibitor Bortezomib Sensitizes AML with Myelomonocytic Differentiation to TRAIL Mediated Apoptosis
Cancers 2011, 3(1), 1329-1350; doi:10.3390/cancers3011329
Received: 5 February 2011 / Revised: 15 February 2011 / Accepted: 10 March 2011 / Published: 15 March 2011
Cited by 4 | PDF Full-text (1399 KB) | HTML Full-text | XML Full-text
Abstract
Acute myeloid leukemia (AML) is an aggressive stem cell malignancy that is difficult to treat. There are limitations to the current treatment regimes especially after disease relapse, and therefore new therapeutic agents are urgently required which can overcome drug resistance whilst avoiding unnecessary
[...] Read more.
Acute myeloid leukemia (AML) is an aggressive stem cell malignancy that is difficult to treat. There are limitations to the current treatment regimes especially after disease relapse, and therefore new therapeutic agents are urgently required which can overcome drug resistance whilst avoiding unnecessary toxicity. Among newer targeted agents, both tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL) and proteasome inhibitors show particular promise. In this report we show that a combination of the proteasome inhibitor bortezomib and TRAIL is effective against AML cell lines, in particular, AML cell lines displaying myelomonocytic/monocytic phenotype (M4/M5 AML based on FAB classification), which account for 20-30% of AML cases. We show that the underlying mechanism of sensitization is at least in part due to bortezomib mediated downregulation of c-FLIP and XIAP, which is likely to be regulated by NF-κB. Blockage of NF-κB activation with BMS-345541 equally sensitized myelomonocytic AML cell lines and primary AML blasts to TRAIL. Full article
(This article belongs to the Special Issue Cell Death and Cancer)
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Review

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Open AccessReview Radical Decisions in Cancer: Redox Control of Cell Growth and Death
Cancers 2012, 4(2), 442-474; doi:10.3390/cancers4020442
Received: 27 March 2012 / Revised: 28 March 2012 / Accepted: 10 April 2012 / Published: 25 April 2012
Cited by 16 | PDF Full-text (341 KB) | HTML Full-text | XML Full-text
Abstract
Free radicals play a key role in many physiological decisions in cells. Since free radicals are toxic to cellular components, it is known that they cause DNA damage, contribute to DNA instability and mutation and thus favor carcinogenesis. However, nowadays it is assumed
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Free radicals play a key role in many physiological decisions in cells. Since free radicals are toxic to cellular components, it is known that they cause DNA damage, contribute to DNA instability and mutation and thus favor carcinogenesis. However, nowadays it is assumed that free radicals play a further complex role in cancer. Low levels of free radicals and steady state levels of antioxidant enzymes are responsible for the fine tuning of redox status inside cells. A change in redox state is a way to modify the physiological status of the cell, in fact, a more reduced status is found in resting cells while a more oxidative status is associated with proliferative cells. The mechanisms by which redox status can change the proliferative activity of cancer cells are related to transcriptional and posttranscriptional modifications of proteins that play a critical role in cell cycle control. Since cancer cells show higher levels of free radicals compared with their normal counterparts, it is believed that the anti-oxidative stress mechanism is also increased in cancer cells. In fact, the levels of some of the most important antioxidant enzymes are elevated in advanced status of some types of tumors. Anti-cancer treatment is compromised by survival mechanisms in cancer cells and collateral damage in normal non-pathological tissues. Though some resistance mechanisms have been described, they do not yet explain why treatment of cancer fails in several tumors. Given that some antitumoral treatments are based on the generation of free radicals, we will discuss in this review the possible role of antioxidant enzymes in the survival mechanism in cancer cells and then, its participation in the failure of cancer treatments. Full article
(This article belongs to the Special Issue Cell Death and Cancer)
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Open AccessReview Inducible Hsp70 in the Regulation of Cancer Cell Survival: Analysis of Chaperone Induction, Expression and Activity
Cancers 2011, 3(4), 3921-3956; doi:10.3390/cancers3043921
Received: 30 June 2011 / Revised: 26 September 2011 / Accepted: 10 October 2011 / Published: 21 October 2011
Cited by 13 | PDF Full-text (885 KB) | HTML Full-text | XML Full-text
Abstract
Understanding the mechanisms that control stress is central to realize how cells respond to environmental and physiological insults. All the more important is to reveal how tumour cells withstand their harsher growth conditions and cope with drug-induced apoptosis, since resistance to chemotherapy is
[...] Read more.
Understanding the mechanisms that control stress is central to realize how cells respond to environmental and physiological insults. All the more important is to reveal how tumour cells withstand their harsher growth conditions and cope with drug-induced apoptosis, since resistance to chemotherapy is the foremost complication when curing cancer. Intensive research on tumour biology over the past number of years has provided significant insights into the molecular events that occur during oncogenesis, and resistance to anti-cancer drugs has been shown to often rely on stress response and expression of inducible heat shock proteins (HSPs). However, with respect to the mechanisms guarding cancer cells against proteotoxic stresses and the modulatory effects that allow their survival, much remains to be defined. Heat shock proteins are molecules responsible for folding newly synthesized polypeptides under physiological conditions and misfolded proteins under stress, but their role in maintaining the transformed phenotype often goes beyond their conventional chaperone activity. Expression of inducible HSPs is known to correlate with limited sensitivity to apoptosis induced by diverse cytotoxic agents and dismal prognosis of several tumour types, however whether cancer cells survive because of the constitutive expression of heat shock proteins or the ability to induce them when adapting to the hostile microenvironment remains to be elucidated. Clear is that tumours appear nowadays more “addicted” to heat shock proteins than previously envisaged, and targeting HSPs represents a powerful approach and a future challenge for sensitizing tumours to therapy. This review will focus on the anti-apoptotic role of heat shock 70kDa protein (Hsp70), and how regulatory factors that control inducible Hsp70 synthesis, expression and activity may be relevant for response to stress and survival of cancer cells. Full article
(This article belongs to the Special Issue Cell Death and Cancer)
Open AccessReview Mechanisms and Therapeutic Implications of Cell Death Induction by Indole Compounds
Cancers 2011, 3(3), 2955-2974; doi:10.3390/cancers3032955
Received: 3 June 2011 / Revised: 7 July 2011 / Accepted: 14 July 2011 / Published: 19 July 2011
Cited by 16 | PDF Full-text (290 KB) | HTML Full-text | XML Full-text
Abstract
Indole compounds, obtained from cruciferous vegetables, are well-known for their anti-cancer properties. In particular, indole-3-carbinol (I3C) and its dimeric product, 3,3´-diindolylmethane (DIM), have been widely investigated for their effectiveness against a number of human cancers in vitro as well as in vivo.
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Indole compounds, obtained from cruciferous vegetables, are well-known for their anti-cancer properties. In particular, indole-3-carbinol (I3C) and its dimeric product, 3,3´-diindolylmethane (DIM), have been widely investigated for their effectiveness against a number of human cancers in vitro as well as in vivo. These compounds are effective inducers of apoptosis and the accumulating evidence documenting their ability to modulate multiple cellular signaling pathways is a testimony to their pleiotropic behavior. Here we attempt to update current understanding on the various mechanisms that are responsible for the apoptosis-inducing effects by these compounds. The significance of apoptosis-induction as a desirable attribute of anti-cancer agents such as indole compounds cannot be overstated. However, an equally intriguing property of these compounds is their ability to sensitize cancer cells to standard chemotherapeutic agents. Such chemosensitizing effects of indole compounds can potentially have major clinical implications because these non-toxic compounds can reduce the toxicity and drug-resistance associated with available chemotherapies. Combinational therapy is increasingly being realized to be better than single agent therapy and, through this review article, we aim to provide a rationale behind combination of natural compounds such as indoles with conventional therapeutics. Full article
(This article belongs to the Special Issue Cell Death and Cancer)
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Open AccessReview Cell Death Pathways in Photodynamic Therapy of Cancer
Cancers 2011, 3(2), 2516-2539; doi:10.3390/cancers3022516
Received: 24 March 2011 / Revised: 26 April 2011 / Accepted: 3 May 2011 / Published: 3 June 2011
Cited by 122 | PDF Full-text (655 KB) | HTML Full-text | XML Full-text
Abstract
Photodynamic therapy (PDT) is an emerging cancer therapy that uses the combination of non-toxic dyes or photosensitizers (PS) and harmless visible light to produce reactive oxygen species and destroy tumors. The PS can be localized in various organelles such as mitochondria, lysosomes, endoplasmic
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Photodynamic therapy (PDT) is an emerging cancer therapy that uses the combination of non-toxic dyes or photosensitizers (PS) and harmless visible light to produce reactive oxygen species and destroy tumors. The PS can be localized in various organelles such as mitochondria, lysosomes, endoplasmic reticulum, Golgi apparatus and plasma membranes and this sub-cellular location governs much of the signaling that occurs after PDT. There is an acute stress response that leads to changes in calcium and lipid metabolism and causes the production of cytokines and stress response mediators. Enzymes (particularly protein kinases) are activated and transcription factors are expressed. Many of the cellular responses center on mitochondria and frequently lead to induction of apoptosis by the mitochondrial pathway involving caspase activation and release of cytochrome c. Certain specific proteins (such as Bcl-2) are damaged by PDT-induced oxidation thereby increasing apoptosis, and a build-up of oxidized proteins leads to an ER-stress response that may be increased by proteasome inhibition. Autophagy plays a role in either inhibiting or enhancing cell death after PDT. Full article
(This article belongs to the Special Issue Cell Death and Cancer)
Open AccessReview Roles of StearoylCoA Desaturase-1 in the Regulation of Cancer Cell Growth, Survival and Tumorigenesis
Cancers 2011, 3(2), 2462-2477; doi:10.3390/cancers3022462
Received: 21 March 2011 / Revised: 27 April 2011 / Accepted: 11 May 2011 / Published: 20 May 2011
Cited by 18 | PDF Full-text (299 KB) | HTML Full-text | XML Full-text
Abstract
The development and maintenance of defining features of cancer, such as unremitting cell proliferation, evasion of programmed cell death, and the capacity for colonizing local tissues and distant organs, demand a massive production of structural, signaling and energy-storing lipid biomolecules of appropriate fatty
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The development and maintenance of defining features of cancer, such as unremitting cell proliferation, evasion of programmed cell death, and the capacity for colonizing local tissues and distant organs, demand a massive production of structural, signaling and energy-storing lipid biomolecules of appropriate fatty acid composition. Due to constitutive activation of fatty acid biosynthesis, cancer cell lipids are enriched with saturated (SFA) and, in particular, monounsaturated fatty acids (MUFA), which are generated by StearoylCoA desaturase-1, the main enzyme that transforms SFA into MUFA. An increasing number of experimental and epidemiological studies suggest that high levels of SCD1 activity is a major factor in establishing the biochemical and metabolic perturbations that favors the oncogenic process. This review examines evidence that suggests the critical implication of SCD1 in the modulation of multiple biological mechanisms, specifically lipid biosynthesis and proliferation and survival signaling pathways that contribute to the development and progression of cancer. Full article
(This article belongs to the Special Issue Cell Death and Cancer)
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Open AccessReview Colorectal Cancer Stem Cells and Cell Death
Cancers 2011, 3(2), 1929-1946; doi:10.3390/cancers3021929
Received: 30 December 2010 / Revised: 21 March 2011 / Accepted: 6 April 2011 / Published: 11 April 2011
Cited by 7 | PDF Full-text (394 KB) | HTML Full-text | XML Full-text
Abstract
Nowadays it is reported that, similarly to other solid tumors, colorectal cancer is sustained by a rare subset of cancer stem–like cells (CSCs), which survive conventional anticancer treatments, thanks to efficient mechanisms allowing escape from apoptosis, triggering tumor recurrence. To improve patient outcomes,
[...] Read more.
Nowadays it is reported that, similarly to other solid tumors, colorectal cancer is sustained by a rare subset of cancer stem–like cells (CSCs), which survive conventional anticancer treatments, thanks to efficient mechanisms allowing escape from apoptosis, triggering tumor recurrence. To improve patient outcomes, conventional anticancer therapies have to be replaced with specific approaches targeting CSCs. In this review we provide strong support that BMP4 is an innovative therapeutic approach to prevent colon cancer growth increasing differentiation markers expression and apoptosis. Recent data suggest that in colorectal CSCs, protection from apoptosis is achieved by interleukin-4 (IL-4) autocrine production through upregulation of antiapoptotic mediators, including survivin. Consequently, IL-4 neutralization could deregulate survivin expression and localization inducing chemosensitivity of the colon CSCs pool. Full article
(This article belongs to the Special Issue Cell Death and Cancer)
Open AccessReview Apoptosis and DNA Methylation
Cancers 2011, 3(2), 1798-1820; doi:10.3390/cancers3021798
Received: 16 February 2011 / Revised: 11 March 2011 / Accepted: 11 March 2011 / Published: 1 April 2011
Cited by 6 | PDF Full-text (793 KB) | HTML Full-text | XML Full-text
Abstract
Epigenetic mechanisms assist in maintaining gene expression patterns and cellular properties in developing and adult tissues. The molecular pathology of disease states frequently includes perturbation of DNA and histone methylation patterns, which can activate apoptotic pathways associated with maintenance of genome integrity. This
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Epigenetic mechanisms assist in maintaining gene expression patterns and cellular properties in developing and adult tissues. The molecular pathology of disease states frequently includes perturbation of DNA and histone methylation patterns, which can activate apoptotic pathways associated with maintenance of genome integrity. This perspective focuses on the pathways linking DNA methyltransferases and methyl-CpG binding proteins to apoptosis, and includes new bioinformatic analyses to characterize the evolutionary origin of two G/T mismatch-specific thymine DNA glycosylases, MBD4 and TDG. Full article
(This article belongs to the Special Issue Cell Death and Cancer)
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Open AccessReview The Role of Nrf2 and Cytoprotection in Regulating Chemotherapy Resistance of Human Leukemia Cells
Cancers 2011, 3(2), 1605-1621; doi:10.3390/cancers3021605
Received: 10 January 2011 / Revised: 18 February 2011 / Accepted: 7 March 2011 / Published: 29 March 2011
Cited by 18 | PDF Full-text (309 KB) | HTML Full-text | XML Full-text
Abstract
The Nrf2 anti-oxidant response element (ARE) pathway plays an important role in regulating cellular anti-oxidants. Under normal cellular conditions Nrf2 can be described as an anti-tumor molecule due to its induction of cytoprotective genes which protect cells from electrophile and oxidative damage. However
[...] Read more.
The Nrf2 anti-oxidant response element (ARE) pathway plays an important role in regulating cellular anti-oxidants. Under normal cellular conditions Nrf2 can be described as an anti-tumor molecule due to its induction of cytoprotective genes which protect cells from electrophile and oxidative damage. However in cancerous cells, Nrf2 takes on a pro-tumoral identity as the same cytoprotective genes can enhance resistance of those cancer cells to chemotherapeutic drugs. Such Nrf2-regulated cytoprotective genes include heme oxygenase-1 (HO-1), which has been shown to protect human leukemia cells from apoptotic signals. Moreover, a relationship between Nrf2 and the nuclear factor-κB (NF-κB) signaling pathway has been recently identified, and is now recognized as an important cross-talk mechanism by which Nrf2 can overcome apoptosis and provide cells with reduced sensitivity towards chemotherapeutic agents. In recent years a number of important research papers have highlighted the role of Nrf2 in providing protection against both current and new chemotherapeutic drugs in blood cancer. This review will provide a synopsis of these research papers with an aim to carefully consider if targeting Nrf2 in combination with current or new chemotherapeutics is a viable strategy in the more effective treatment of blood cancers. Full article
(This article belongs to the Special Issue Cell Death and Cancer)
Open AccessReview Targeting the Anti-Apoptotic Protein c-FLIP for Cancer Therapy
Cancers 2011, 3(2), 1639-1671; doi:10.3390/cancers3021639
Received: 26 February 2011 / Revised: 15 March 2011 / Accepted: 16 March 2011 / Published: 29 March 2011
Cited by 55 | PDF Full-text (1033 KB) | HTML Full-text | XML Full-text
Abstract
Cellular FLICE (FADD-like IL-1beta-converting enzyme)-inhibitory protein (c-FLIP) is a major resistance factor and critical anti-apoptotic regulator that inhibits tumor necrosis factor-alpha (TNF-alpha), Fas-L, and TNF-related apoptosis-inducing ligand (TRAIL)-induced apoptosis as well as chemotherapy-triggered apoptosis in malignant cells. c-FLIP is expressed as long (c-FLIP
[...] Read more.
Cellular FLICE (FADD-like IL-1beta-converting enzyme)-inhibitory protein (c-FLIP) is a major resistance factor and critical anti-apoptotic regulator that inhibits tumor necrosis factor-alpha (TNF-alpha), Fas-L, and TNF-related apoptosis-inducing ligand (TRAIL)-induced apoptosis as well as chemotherapy-triggered apoptosis in malignant cells. c-FLIP is expressed as long (c-FLIPL), short (c-FLIPS), and c-FLIPR splice variants in human cells. c-FLIP binds to FADD and/or caspase-8 or -10 in a ligand-dependent and-independent fashion, which in turn prevents death-inducing signaling complex (DISC) formation and subsequent activation of the caspase cascade. Moreover, c-FLIPL and c-FLIPS are known to have multifunctional roles in various signaling pathways, as well as activating and/or upregulating several cytoprotective signaling molecules. Upregulation of c-FLIP has been found in various tumor types, and its downregulation has been shown to restore apoptosis triggered by cytokines and various chemotherapeutic agents. Hence, c-FLIP is an important target for cancer therapy. For example, small interfering RNAs (siRNAs) that specifically knockdown the expression of c-FLIPL in diverse human cancer cell lines augmented TRAIL-induced DISC recruitment and increased the efficacy of chemotherapeutic agents, thereby enhancing effector caspase stimulation and apoptosis. Moreover, small molecules causing degradation of c-FLIP as well as decreasing mRNA and protein levels of c-FLIPL and c-FLIPS splice variants have been found, and efforts are underway to develop other c-FLIP-targeted cancer therapies. This review focuses on (1) the functional role of c-FLIP splice variants in preventing apoptosis and inducing cytokine and drug resistance; (2) the molecular mechanisms that regulate c-FLIP expression; and (3) strategies to inhibit c-FLIP expression and function. Full article
(This article belongs to the Special Issue Cell Death and Cancer)
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Open AccessReview Role of Methionine Adenosyltransferase Genes in Hepatocarcinogenesis
Cancers 2011, 3(2), 1480-1497; doi:10.3390/cancers3021480
Received: 16 December 2010 / Revised: 27 January 2011 / Accepted: 30 January 2011 / Published: 24 March 2011
Cited by 7 | PDF Full-text (272 KB) | HTML Full-text | XML Full-text
Abstract
Hepatocellular carcinoma (HCC) is the most common primary malignant tumor of the liver. Detection of HCC can be difficult, as most of the patients who develop this tumor have no symptoms other than those related to their longstanding liver disease. There is an
[...] Read more.
Hepatocellular carcinoma (HCC) is the most common primary malignant tumor of the liver. Detection of HCC can be difficult, as most of the patients who develop this tumor have no symptoms other than those related to their longstanding liver disease. There is an urgent need to understand the molecular mechanisms that are responsible for the development of this disease so that appropriate therapies can be designed. Methionine adenosyltransferase (MAT) is an essential enzyme required for the biosynthesis of S-adenosylmethionine (AdoMet), an important methyl donor in the cell. Alterations in the expression of MAT genes and a decline in AdoMet biosynthesis are known to be associated with liver injury, cirrhosis and HCC. This review focuses on the role of MAT genes in HCC development and the scope for therapeutic strategies using these genes. Full article
(This article belongs to the Special Issue Cell Death and Cancer)
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Open AccessReview To Die or to Survive, a Fatal Question for the Destiny of Prostate Cancer Cells after Androgen Deprivation Therapy
Cancers 2011, 3(2), 1498-1512; doi:10.3390/cancers3021498
Received: 4 February 2011 / Revised: 16 March 2011 / Accepted: 17 March 2011 / Published: 24 March 2011
Cited by 1 | PDF Full-text (217 KB) | HTML Full-text | XML Full-text
Abstract
Prostate cancer is the most frequently diagnosed non-skin cancer in adult males in North America and is the second leading cause of cancer-related mortality.For locally advanced or metastatic disease, androgen deprivation, through medical or surgical castration, is the primary treatment to induce
[...] Read more.
Prostate cancer is the most frequently diagnosed non-skin cancer in adult males in North America and is the second leading cause of cancer-related mortality. For locally advanced or metastatic disease, androgen deprivation, through medical or surgical castration, is the primary treatment to induce prostate cancer cell death and extend patient survival. However, the vast majority of cancers progress to a castration-resistant/androgen-independent state where the cell death processes are no longer active. This review describes the main cell death processes, apoptosis, autophagy, necrosis and necroptosis, which may be activated in prostate cancers after androgen deprivation therapy as well as the molecular mechanisms through which the cancers progress to become castration resistant. In particular, the central role of persistent androgen receptor (AR)-mediated signaling and AR crosstalk with other critical cell signaling pathways, including (i) the PI3K/Akt pathway, (ii) receptor tyrosine kinases, (iii) the p38 MAPK pathway, and (iv) the Wnt/β-catenin pathway, as well as reactivation of AR by de novo synthesized androgen are discussed in this context. Understanding the molecular changes that subvert normal cell death mechanisms and thereby compromise the survival of prostate cancer patients continues to be a major challenge. Full article
(This article belongs to the Special Issue Cell Death and Cancer)
Open AccessReview Cisplatin as an Anti-Tumor Drug: Cellular Mechanisms of Activity, Drug Resistance and Induced Side Effects
Cancers 2011, 3(1), 1351-1371; doi:10.3390/cancers3011351
Received: 14 January 2011 / Revised: 28 February 2011 / Accepted: 3 March 2011 / Published: 15 March 2011
Cited by 242 | PDF Full-text (329 KB) | HTML Full-text | XML Full-text
Abstract
Platinum complexes are clinically used as adjuvant therapy of cancers aiming to induce tumor cell death. Depending on cell type and concentration, cisplatin induces cytotoxicity, e.g., by interference with transcription and/or DNA replication mechanisms. Additionally, cisplatin damages tumors via induction of apoptosis, mediated
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Platinum complexes are clinically used as adjuvant therapy of cancers aiming to induce tumor cell death. Depending on cell type and concentration, cisplatin induces cytotoxicity, e.g., by interference with transcription and/or DNA replication mechanisms. Additionally, cisplatin damages tumors via induction of apoptosis, mediated by the activation of various signal transduction pathways, including calcium signaling, death receptor signaling, and the activation of mitochondrial pathways. Unfortunately, neither cytotoxicity nor apoptosis are exclusively induced in cancer cells, thus, cisplatin might also lead to diverse side-effects such as neuro- and/or renal-toxicity or bone marrow-suppression. Moreover, the binding of cisplatin to proteins and enzymes may modulate its biochemical mechanism of action. While a combination-chemotherapy with cisplatin is a cornerstone for the treatment of multiple cancers, the challenge is that cancer cells could become cisplatin-resistant. Numerous mechanisms of cisplatin resistance were described including changes in cellular uptake, drug efflux, increased detoxification, inhibition of apoptosis and increased DNA repair. To minimize cisplatin resistance, combinatorial therapies were developed and have proven more effective to defeat cancers. Thus, understanding of the biochemical mechanisms triggered by cisplatin in tumor cells may lead to the design of more efficient platinum derivates (or other drugs) and might provide new therapeutic strategies and reduce side effects. Full article
(This article belongs to the Special Issue Cell Death and Cancer)
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Open AccessReview Glutathione in Cancer Cell Death
Cancers 2011, 3(1), 1285-1310; doi:10.3390/cancers3011285
Received: 30 December 2010 / Revised: 22 February 2011 / Accepted: 9 March 2011 / Published: 11 March 2011
Cited by 62 | PDF Full-text (641 KB) | HTML Full-text | XML Full-text
Abstract
Glutathione (L-γ-glutamyl-L-cysteinyl-glycine; GSH) in cancer cells is particularly relevant in the regulation of carcinogenic mechanisms; sensitivity against cytotoxic drugs, ionizing radiations, and some cytokines; DNA synthesis; and cell proliferation and death. The intracellular thiol redox state (controlled by GSH) is one
[...] Read more.
Glutathione (L-γ-glutamyl-L-cysteinyl-glycine; GSH) in cancer cells is particularly relevant in the regulation of carcinogenic mechanisms; sensitivity against cytotoxic drugs, ionizing radiations, and some cytokines; DNA synthesis; and cell proliferation and death. The intracellular thiol redox state (controlled by GSH) is one of the endogenous effectors involved in regulating the mitochondrial permeability transition pore complex and, in consequence, thiol oxidation can be a causal factor in the mitochondrion-based mechanism that leads to cell death. Nevertheless GSH depletion is a common feature not only of apoptosis but also of other types of cell death. Indeed rates of GSH synthesis and fluxes regulate its levels in cellular compartments, and potentially influence switches among different mechanisms of death. How changes in gene expression, post-translational modifications of proteins, and signaling cascades are implicated will be discussed. Furthermore, this review will finally analyze whether GSH depletion may facilitate cancer cell death under in vivo conditions, and how this can be applied to cancer therapy. Full article
(This article belongs to the Special Issue Cell Death and Cancer)
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Open AccessReview Implication of Heat Shock Factors in Tumorigenesis: Therapeutical Potential
Cancers 2011, 3(1), 1158-1181; doi:10.3390/cancers3011158
Received: 30 January 2011 / Accepted: 23 February 2011 / Published: 7 March 2011
Cited by 14 | PDF Full-text (620 KB) | HTML Full-text | XML Full-text
Abstract
Heat Shock Factors (HSF) form a family of transcription factors (four in mammals) which were named according to the discovery of their activation by a heat shock. HSFs trigger the expression of genes encoding Heat Shock Proteins (HSPs) that function as molecular chaperones,
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Heat Shock Factors (HSF) form a family of transcription factors (four in mammals) which were named according to the discovery of their activation by a heat shock. HSFs trigger the expression of genes encoding Heat Shock Proteins (HSPs) that function as molecular chaperones, contributing to establish a cytoprotective state to various proteotoxic stresses and in pathological conditions. Increasing evidence indicates that this ancient transcriptional protective program acts genome-widely and performs unexpected functions in the absence of experimentally defined stress. Indeed, HSFs are able to re-shape cellular pathways controlling longevity, growth, metabolism and development. The most well studied HSF, HSF1, has been found at elevated levels in tumors with high metastatic potential and is associated with poor prognosis. This is partly explained by the above-mentioned cytoprotective (HSP-dependent) function that may enable cancer cells to adapt to the initial oncogenic stress and to support malignant transformation. Nevertheless, HSF1 operates as major multifaceted enhancers of tumorigenesis through, not only the induction of classical heat shock genes, but also of “non-classical” targets. Indeed, in cancer cells, HSF1 regulates genes involved in core cellular functions including proliferation, survival, migration, protein synthesis, signal transduction, and glucose metabolism, making HSF1 a very attractive target in cancer therapy. In this review, we describe the different physiological roles of HSFs as well as the recent discoveries in term of non-cogenic potential of these HSFs, more specifically associated to the activation of “non-classical” HSF target genes. We also present an update on the compounds with potent HSF1-modulating activity of potential interest as anti-cancer therapeutic agents. Full article
(This article belongs to the Special Issue Cell Death and Cancer)
Open AccessReview Role of p53 in Cell Death and Human Cancers
Cancers 2011, 3(1), 994-1013; doi:10.3390/cancers3010994
Received: 7 December 2010 / Revised: 22 February 2011 / Accepted: 22 February 2011 / Published: 3 March 2011
Cited by 21 | PDF Full-text (293 KB) | HTML Full-text | XML Full-text
Abstract
p53 is a nuclear transcription factor with a pro-apoptotic function. Since over 50% of human cancers carry loss of function mutations in p53 gene, p53 has been considered to be one of the classical type tumor suppressors. Mutant p53 acts as the dominant-negative
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p53 is a nuclear transcription factor with a pro-apoptotic function. Since over 50% of human cancers carry loss of function mutations in p53 gene, p53 has been considered to be one of the classical type tumor suppressors. Mutant p53 acts as the dominant-negative inhibitor toward wild-type p53. Indeed, mutant p53 has an oncogenic potential. In some cases, malignant cancer cells bearing p53 mutations display a chemo-resistant phenotype. In response to a variety of cellular stresses such as DNA damage, p53 is induced to accumulate in cell nucleus to exert its pro-apoptotic function. Activated p53 promotes cell cycle arrest to allow DNA repair and/or apoptosis to prevent the propagation of cells with serious DNA damage through the transactivation of its target genes implicated in the induction of cell cycle arrest and/or apoptosis. Thus, the DNA-binding activity of p53 is tightly linked to its tumor suppressive function. In the present review article, we describe the regulatory mechanisms of p53 and also p53-mediated therapeutic strategies to cure malignant cancers. Full article
(This article belongs to the Special Issue Cell Death and Cancer)
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Open AccessReview Cell-Centric View of Apoptosis and Apoptotic Cell Death-Inducing Antitumoral Strategies
Cancers 2011, 3(1), 1042-1080; doi:10.3390/cancers3011042
Received: 8 January 2011 / Revised: 18 February 2011 / Accepted: 1 March 2011 / Published: 3 March 2011
Cited by 6 | PDF Full-text (6230 KB) | HTML Full-text | XML Full-text
Abstract
Programmed cell death and especially apoptotic cell death, occurs under physiological conditions and is also desirable under pathological circumstances. However, the more we learn about cellular signaling cascades, the less plausible it becomes to find restricted and well-limited signaling pathways. In this context,
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Programmed cell death and especially apoptotic cell death, occurs under physiological conditions and is also desirable under pathological circumstances. However, the more we learn about cellular signaling cascades, the less plausible it becomes to find restricted and well-limited signaling pathways. In this context, an extensive description of pathway-connections is necessary in order to point out the main regulatory molecules as well as to select the most appropriate therapeutic targets. On the other hand, irregularities in programmed cell death pathways often lead to tumor development and cancer-related mortality is projected to continue increasing despite the effort to develop more active and selective antitumoral compounds. In fact, tumor cell plasticity represents a major challenge in chemotherapy and improvement on anticancer therapies seems to rely on appropriate drug combinations. An overview of the current status regarding apoptotic pathways as well as available chemotherapeutic compounds provides a new perspective of possible future anticancer strategies. Full article
(This article belongs to the Special Issue Cell Death and Cancer)
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Open AccessReview Advances in Viral Vector-Based TRAIL Gene Therapy for Cancer
Cancers 2011, 3(1), 603-620; doi:10.3390/cancers3010603
Received: 29 December 2010 / Revised: 28 January 2011 / Accepted: 30 January 2011 / Published: 10 February 2011
Cited by 6 | PDF Full-text (270 KB) | HTML Full-text | XML Full-text
Abstract
Numerous biologic approaches are being investigated as anti-cancer therapies in an attempt to induce tumor regression while circumventing the toxic side effects associated with standard chemo- or radiotherapies. Among these, tumor necrosis factor–related apoptosis-inducing ligand (TRAIL) has shown particular promise in pre-clinical and
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Numerous biologic approaches are being investigated as anti-cancer therapies in an attempt to induce tumor regression while circumventing the toxic side effects associated with standard chemo- or radiotherapies. Among these, tumor necrosis factor–related apoptosis-inducing ligand (TRAIL) has shown particular promise in pre-clinical and early clinical trials, due to its preferential ability to induce apoptotic cell death in cancer cells and its minimal toxicity. One limitation of TRAIL use is the fact that many tumor types display an inherent resistance to TRAIL-induced apoptosis. To circumvent this problem, researchers have explored a number of strategies to optimize TRAIL delivery and to improve its efficacy via co-administration with other anti-cancer agents. In this review, we will focus on TRAIL-based gene therapy approaches for the treatment of malignancies. We will discuss the main viral vectors that are being used for TRAIL gene therapy and the strategies that are currently being attempted to improve the efficacy of TRAIL as an anti-cancer therapeutic. Full article
(This article belongs to the Special Issue Cell Death and Cancer)
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Open AccessReview Nerve Growth Factor in Cancer Cell Death and Survival
Cancers 2011, 3(1), 510-530; doi:10.3390/cancers3010510
Received: 7 December 2010 / Revised: 24 January 2011 / Accepted: 25 January 2011 / Published: 1 February 2011
Cited by 27 | PDF Full-text (444 KB) | HTML Full-text | XML Full-text
Abstract
One of the major challenges for cancer therapeutics is the resistance of many tumor cells to induction of cell death due to pro-survival signaling in the cancer cells. Here we review the growing literature which shows that neurotrophins contribute to pro-survival signaling in
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One of the major challenges for cancer therapeutics is the resistance of many tumor cells to induction of cell death due to pro-survival signaling in the cancer cells. Here we review the growing literature which shows that neurotrophins contribute to pro-survival signaling in many different types of cancer. In particular, nerve growth factor, the archetypal neurotrophin, has been shown to play a role in tumorigenesis over the past decade. Nerve growth factor mediates its effects through its two cognate receptors, TrkA, a receptor tyrosine kinase and p75NTR, a member of the death receptor superfamily. Depending on the tumor origin, pro-survival signaling can be mediated by TrkA receptors or by p75NTR. For example, in breast cancer the aberrant expression of nerve growth factor stimulates proliferative signaling through TrkA and pro-survival signaling through p75NTR. This latter signaling through p75NTR promotes increased resistance to the induction of cell death by chemotherapeutic treatments. In contrast, in prostate cells the p75NTR mediates cell death and prevents metastasis. In prostate cancer, expression of this receptor is lost, which contributes to tumor progression by allowing cells to survive, proliferate and metastasize. This review focuses on our current knowledge of neurotrophin signaling in cancer, with a particular emphasis on nerve growth factor regulation of cell death and survival in cancer. Full article
(This article belongs to the Special Issue Cell Death and Cancer)
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Open AccessReview Protein Kinase C: An Attractive Target for Cancer Therapy
Cancers 2011, 3(1), 531-567; doi:10.3390/cancers3010531
Received: 23 December 2010 / Revised: 19 January 2011 / Accepted: 26 January 2011 / Published: 1 February 2011
Cited by 4 | PDF Full-text (545 KB) | HTML Full-text | XML Full-text
Abstract
Apoptosis plays an important role during all stages of carcinogenesis and the development of chemoresistance in tumor cells may be due to their selective defects in the intracellular signaling proteins, central to apoptotic pathways. Consequently, many studies have focused on rendering the chemotherapy
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Apoptosis plays an important role during all stages of carcinogenesis and the development of chemoresistance in tumor cells may be due to their selective defects in the intracellular signaling proteins, central to apoptotic pathways. Consequently, many studies have focused on rendering the chemotherapy more effective in order to prevent chemoresistance and pre-clinical and clinical data has suggested that protein kinase C (PKC) may represent an attractive target for cancer therapy. Therefore, a complete understanding of how PKC regulates apoptosis and chemoresistance may lead to obtaining a PKC-based therapy that is able to reduce drug dosages and to prevent the development of chemoresistance. Full article
(This article belongs to the Special Issue Cell Death and Cancer)
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Open AccessReview Parathyroid Hormone-Related Protein (PTHrP): A Key Regulator of Life/Death Decisions by Tumor Cells with Potential Clinical Applications
Cancers 2011, 3(1), 396-407; doi:10.3390/cancers3010396
Received: 3 December 2010 / Revised: 27 December 2010 / Accepted: 14 January 2011 / Published: 20 January 2011
Cited by 6 | PDF Full-text (189 KB) | HTML Full-text | XML Full-text
Abstract
Parathyroid hormone-related protein (PTHrP), classically regarded as the mediator of the humoral hypercalcemia of malignancy syndrome, is a polyhormone that undergoes proteolytic processing into smaller bioactive forms. These bioactive forms comprise an N-terminal- as well as midregion- and C-terminal peptides, which have been
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Parathyroid hormone-related protein (PTHrP), classically regarded as the mediator of the humoral hypercalcemia of malignancy syndrome, is a polyhormone that undergoes proteolytic processing into smaller bioactive forms. These bioactive forms comprise an N-terminal- as well as midregion- and C-terminal peptides, which have been shown to regulate various biological events, such as survival, proliferation and differentiation, in diverse cell model systems, both normal and pathological. A number of experimental data have demonstrated that PTHrP is also able to modulate tumor-relevant phenotypic expressions, thereby playing a role in early and advanced tumorigenesis, and in the response to treatment. In particular, interest has mainly been focused on the effects of PTHrP on cell proliferation/apoptosis, migration and invasion, which are the main roles involved in cancer development in vivo. The objective of this review is to discuss collectively the literature data on the molecular and biochemical basis of the mechanisms underlying the different, and sometimes opposite, effects exerted by PTHrP on various neoplastic cytotypes, with some final comments on both present and potential utilization of PTHrP as a target for anti-cancer therapy. Full article
(This article belongs to the Special Issue Cell Death and Cancer)
Open AccessReview Nuclear Receptor Small Heterodimer Partner in Apoptosis Signaling and Liver Cancer
Cancers 2011, 3(1), 198-212; doi:10.3390/cancers3010198
Received: 30 November 2010 / Revised: 30 December 2010 / Accepted: 4 January 2011 / Published: 5 January 2011
Cited by 7 | PDF Full-text (258 KB) | HTML Full-text | XML Full-text
Abstract
Small heterodimer partner (SHP, NR0B2) is a unique orphan nuclear receptor that contains the dimerization and a putative ligand-binding domain, but lacks the conserved DNA binding domain. SHP exerts its physiological function as an inhibitor of gene transcription through physical interaction
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Small heterodimer partner (SHP, NR0B2) is a unique orphan nuclear receptor that contains the dimerization and a putative ligand-binding domain, but lacks the conserved DNA binding domain. SHP exerts its physiological function as an inhibitor of gene transcription through physical interaction with multiple nuclear receptors and transcriptional factors. SHP is a critical transcriptional regulator affecting diverse biological functions, including bile acid, cholesterol and lipid metabolism, glucose and energy homeostasis, and reproductive biology. Recently, we and others have demonstrated that SHP is an epigenetically regulated transcriptional repressor that suppresses the development of liver cancer. In this review, we summarize recent major findings regarding the role of SHP in cell proliferation, apoptosis, and DNA methylation, and discuss recent progress in understanding the function of SHP as a tumor suppressor in the development of liver cancer. Future study will be focused on identifying SHP associated novel pro-oncogenes and anti-oncogenes in liver cancer progression and applying the knowledge gained on SHP in liver cancer prevention, diagnosis and treatment. Full article
(This article belongs to the Special Issue Cell Death and Cancer)
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Open AccessReview The Enigmatic Roles of Caspases in Tumor Development
Cancers 2010, 2(4), 1952-1979; doi:10.3390/cancers2041952
Received: 8 November 2010 / Revised: 16 November 2010 / Accepted: 23 November 2010 / Published: 24 November 2010
Cited by 9 | PDF Full-text (195 KB) | HTML Full-text | XML Full-text
Abstract
One function ascribed to apoptosis is the suicidal destruction of potentially harmful cells, such as cancerous cells. Hence, their growth depends on evasion of apoptosis, which is considered as one of the hallmarks of cancer. Apoptosis is ultimately carried out by the sequential
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One function ascribed to apoptosis is the suicidal destruction of potentially harmful cells, such as cancerous cells. Hence, their growth depends on evasion of apoptosis, which is considered as one of the hallmarks of cancer. Apoptosis is ultimately carried out by the sequential activation of initiator and executioner caspases, which constitute a family of intracellular proteases involved in dismantling the cell in an ordered fashion. In cancer, therefore, one would anticipate caspases to be frequently rendered inactive, either by gene silencing or by somatic mutations. From clinical data, however, there is little evidence that caspase genes are impaired in cancer. Executioner caspases have only rarely been found mutated or silenced, and also initiator caspases are only affected in particular types of cancer. There is experimental evidence from transgenic mice that certain initiator caspases, such as caspase-8 and -2, might act as tumor suppressors. Loss of the initiator caspase of the intrinsic apoptotic pathway, caspase-9, however, did not promote cellular transformation. These data seem to question a general tumor-suppressive role of caspases. We discuss several possible ways how tumor cells might evade the need for alterations of caspase genes. First, alternative splicing in tumor cells might generate caspase variants that counteract apoptosis. Second, in tumor cells caspases might be kept in check by cellular caspase inhibitors such as c-FLIP or XIAP. Third, pathways upstream of caspase activation might be disrupted in tumor cells. Finally, caspase-independent cell death mechanisms might abrogate the selection pressure for caspase inactivation during tumor development. These scenarios, however, are hardly compatible with the considerable frequency of spontaneous apoptosis occurring in several cancer types. Therefore, alternative concepts might come into play, such as compensatory proliferation. Herein, apoptosis and/or non-apoptotic functions of caspases may even promote tumor development. Moreover, experimental evidence suggests that caspases might play non-apoptotic roles in processes that are crucial for tumorigenesis, such as cell proliferation, migration, or invasion. We thus propose a model wherein caspases are preserved in tumor cells due to their functional contributions to development and progression of tumors. Full article
(This article belongs to the Special Issue Cell Death and Cancer)
Open AccessReview 5-FU Metabolism in Cancer and Orally-Administrable 5-FU Drugs
Cancers 2010, 2(3), 1717-1730; doi:10.3390/cancers2031717
Received: 23 August 2010 / Revised: 14 September 2010 / Accepted: 15 September 2010 / Published: 17 September 2010
Cited by 14 | PDF Full-text (526 KB) | HTML Full-text | XML Full-text
Abstract
5-Fluorouracil (5-FU) is a key anticancer drug that for its broad antitumor activity, as well as for its synergism with other anticancer drugs, has been used to treat various types of malignancies. In chemotherapeutic regimens, 5-FU has been combined with oxaliplatin, irinotecan and
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5-Fluorouracil (5-FU) is a key anticancer drug that for its broad antitumor activity, as well as for its synergism with other anticancer drugs, has been used to treat various types of malignancies. In chemotherapeutic regimens, 5-FU has been combined with oxaliplatin, irinotecan and other drugs as a continuous intravenous infusion. Recent clinical chemotherapy studies have shown that several of the regimens with oral 5-FU drugs are not inferior compared to those involving continuous 5-FU infusion chemotherapy, and it is probable that in some regimens continuous 5-FU infusion can be replaced by oral 5-FU drugs. Historically, both the pharmaceutical industry and academia in Japan have been involved in the development of oral 5-FU drugs, and this review will focus on the current knowledge of 5-FU anabolism and catabolism, and the available information about the various orally-administrable 5-FU drugs, including UFT, S-1 and capecitabine. Clinical studies comparing the efficacy and adverse events of S-1 and capecitabine have been reported, and the accumulated results should be utilized to optimize the treatment of cancer patients. On the other hand, it is essential to elucidate the pharmacokinetic mechanism of each of the newly-developed drugs, to correctly select the drugs for each patient in the clinical setting, and to further develop optimized drug derivatives. Full article
(This article belongs to the Special Issue Cell Death and Cancer)
Open AccessReview The Role of Macrophage Migration Inhibitory Factor (MIF) in Ultraviolet Radiation-Induced Carcinogenesis
Cancers 2010, 2(3), 1555-1564; doi:10.3390/cancers2031555
Received: 23 June 2010 / Revised: 5 August 2010 / Accepted: 6 August 2010 / Published: 9 August 2010
Cited by 4 | PDF Full-text (201 KB) | HTML Full-text | XML Full-text
Abstract
Ultraviolet (UV) radiation is the most common cause of physical injury to the skin due to environmental damage, and UV exposure substantially increases the risk of actinic damage to the skin. The inflammatory changes induced by acute UV exposure include erythema (sunburn) of
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Ultraviolet (UV) radiation is the most common cause of physical injury to the skin due to environmental damage, and UV exposure substantially increases the risk of actinic damage to the skin. The inflammatory changes induced by acute UV exposure include erythema (sunburn) of the skin, while chronic exposure to solar UV radiation causes photo-aging, immunosuppression, and ultimately, carcinogenesis of the skin. After skin damage by UV radiation, the cells are known to secrete many cytokines, including interleukin (IL)-1, IL-6, tumor necrosis factor (TNF)-α. and macrophage migration inhibitory factor (MIF). MIF was originally identified as a lymphokine that concentrates macrophages at inflammatory loci, and is known to be a potent activator of macrophages in vivo. MIF is considered to play an important role in cell-mediated immunity. Since the molecular cloning of MIF cDNA, MIF has been re-evaluated as a proinflammatory cytokine and pituitary-derived hormone that potentiates endotoxemia. MIF is ubiquitously expressed in various tissues, including the skin. Recent studies have suggested a potentially broader role for MIF in growth regulation because of its ability to antagonize p53-mediated gene activation and apoptosis. This article reviews the latest findings on the roles of MIF with regard to UV-induced skin cancer. Full article
(This article belongs to the Special Issue Cell Death and Cancer)
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