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Special Issue "Lipid as a Cancer Therapeutic Target"

A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Oncology".

Deadline for manuscript submissions: 31 March 2020.

Special Issue Editors

Prof. Dr. Elisabetta Albi
E-Mail Website
Guest Editor
Department of Pharmaceutical Science, University of Perugia, 06100 Perugia, Italy
Interests: lipid metabolism; nuclear lipids; cancer; cell proliferation and differentiation; neurodegenerative disorders; liver; brain; thyroid
Prof. Dr. Sabine Groesch
E-Mail
Guest Editor
Institute of Clinical Pharmacology, pharmazentrum frankfurt, Goethe-University Frankfurt, Germany
Interests: Pharmacology, Lipids, Prostaglandins, Sphingolipids, Cancer; Colon, Inflammation
Prof. Dr. Andrea Huwiler
E-Mail
Guest Editor
Institute of Pharmacology, University of Bern, Inselspital, INO-F,CH-3010 Bern, Switzerland
Interests: sphingolipid and prostaglandin signalling in health and disease

Special Issue Information

Dear Colleagues,

Lipids are not only components of cellular membranes but also constitute important signaling molecules. They can influence cellular signaling pathways via binding to extracellular cellular receptors or intracellular molecules, like phosphatases and kinases. Additionally, they can form special membrane domains, which represent important signaling platforms for the activation of membrane-associated proteins. With regard to these multiple cellular functions, lipids are important players in physiological and pathophysiological processes and interesting targets for mostly incurable diseases like cancer. Prostaglandin E2 (PGE2) and sphingosine-1 phosphate (S1P) are well-known lipids that promote cancer growth. However, other lipids are also deregulated in cancer and interfering with the synthesis or binding of these lipids are promising approaches for cancer therapy. This Special Issue will summarize current knowledge of therapeutics that target lipids as a new treatment option for cancer therapy. We invite researchers in the broad field of sphingolipids, cholesterol, prostaglandins, leukotrienes, and phospholipids to contribute to this Special Issue.

Prof. Dr. Andrea Huwiler
Prof. Dr. Elisabetta Albi
Dr. Sabine Groesch
Guest Editors

Manuscript Submission Information

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Keywords

  • sphingolipids
  • cholesterol
  • prostaglandins
  • leukotrienes
  • phospholipids
  • cancer
  • lipid targets
  • lipid metabolism
  • lipid signaling
  • lipid cancer therapy

Published Papers (7 papers)

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Research

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Open AccessArticle
Cytosolic Phospholipase A2 Alpha Regulates TLR Signaling and Migration in Metastatic 4T1 Cells
Int. J. Mol. Sci. 2019, 20(19), 4800; https://doi.org/10.3390/ijms20194800 - 27 Sep 2019
Cited by 1
Abstract
Metastatic disease is the leading cause of death in breast cancer patients. Disrupting the cancer cell’s ability to migrate may be a strategy for hindering metastasis. Cytosolic phospholipase A2 α (cPLA2α), along with downstream proinflammatory and promigratory metabolites, has been implicated in several [...] Read more.
Metastatic disease is the leading cause of death in breast cancer patients. Disrupting the cancer cell’s ability to migrate may be a strategy for hindering metastasis. Cytosolic phospholipase A2 α (cPLA2α), along with downstream proinflammatory and promigratory metabolites, has been implicated in several aspects of tumorigenesis, as well as metastasis, in various types of cancer. In this study, we aim to characterize the response to reduced cPLA2α activity in metastatic versus non-metastatic cells. We employ an isogenic murine cell line pair displaying metastatic (4T1) and non-metastatic (67NR) phenotype to investigate the role of cPLA2α on migration. Furthermore, we elucidate the effect of reduced cPLA2α activity on global gene expression in the metastatic cell line. Enzyme inhibition is achieved by using a competitive pharmacological inhibitor, cPLA2α inhibitor X (CIX). Our data show that 4T1 expresses significantly higher cPLA2α levels as compared to 67NR, and the two cell lines show different sensitivity to the CIX treatment with regards to metabolism and proliferation. Inhibition of cPLA2α at nontoxic concentrations attenuates migration of highly metastatic 4T1 cells, but not non-metastatic 67NR cells. Gene expression analysis indicates that processes such as interferon type I (IFN-I) signaling and cell cycle regulation are key processes regulated by cPLA2a in metastatic 4T1 cells, supporting the findings from the biological assays. This study demonstrates that two isogenic cancer cell lines with different metastatic potential respond differently to reduced cPLA2α activity. In conclusion, we argue that cPLA2α is a potential therapeutic target in cancer and that enzyme inhibition may inhibit metastasis through an anti-migratory mechanism, possibly involving Toll-like receptor signaling and type I interferons. Full article
(This article belongs to the Special Issue Lipid as a Cancer Therapeutic Target)
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Open AccessCommunication
Long and Very-Long-Chain Ceramides Correlate with A More Aggressive Behavior in Skull Base Chordoma Patients
Int. J. Mol. Sci. 2019, 20(18), 4480; https://doi.org/10.3390/ijms20184480 - 11 Sep 2019
Abstract
Background: Skull base chordomas are rare tumors arising from notochord. Sphingolipids analysis is a promising approach in molecular oncology, and it has never been applied in chordomas. Our aim is to investigate chordoma behavior and the role of ceramides. Methods: Ceramides were extracted [...] Read more.
Background: Skull base chordomas are rare tumors arising from notochord. Sphingolipids analysis is a promising approach in molecular oncology, and it has never been applied in chordomas. Our aim is to investigate chordoma behavior and the role of ceramides. Methods: Ceramides were extracted and evaluated by liquid chromatography and mass spectrometry in a cohort of patients with a skull base chordoma. Clinical data were also collected and correlated with ceramide levels. Linear regression and correlation analyses were conducted. Results: Analyzing the association between ceramides level and MIB-1, total ceramides and dihydroceramides showed a strong association (r = 0.7257 and r = 0.6733, respectively) with MIB-1 staining (p = 0.0033 and p = 0.0083, respectively). Among the single ceramide species, Cer C24:1 (r = 0.8814, p ≤ 0.0001), DHCer C24:1 (r = 0.8429, p = 0.0002) and DHCer C18:0 (r = 0.9426, p ≤ 0.0001) showed a significant correlation with MIB-1. Conclusion: Our lipid analysis showed ceramides to be promising tumoral biomarkers in skull base chordomas. Long- and very-long-chain ceramides, such as Cer C24:1 and DHCer C24:1, may be related to a prolonged tumor survival and aggressiveness, and the understanding of their effective biological role will hopefully shed light on the mechanisms of chordoma radio-resistance, tendency to recur, and use of agents targeting ceramide metabolism. Full article
(This article belongs to the Special Issue Lipid as a Cancer Therapeutic Target)
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Open AccessArticle
Gentamicin Targets Acid Sphingomyelinase in Cancer: The Case of the Human Gastric Cancer NCI-N87 Cells
Int. J. Mol. Sci. 2019, 20(18), 4375; https://doi.org/10.3390/ijms20184375 - 06 Sep 2019
Abstract
Emerging literature implicates acid sphingomyelinase in tumor sensitivity/resistance to anticancer treatments. Gentamicin is a drug commonly used as an antimicrobial but its serendipity effects have been shown. Even though many evidences on the role of gentamicin in cancer have been reported, its mechanism [...] Read more.
Emerging literature implicates acid sphingomyelinase in tumor sensitivity/resistance to anticancer treatments. Gentamicin is a drug commonly used as an antimicrobial but its serendipity effects have been shown. Even though many evidences on the role of gentamicin in cancer have been reported, its mechanism of action is poorly understood. Here, we explored acid sphingomyelinase as a possible new target of gentamicin in cancer. Since gastric cancer is one of the most common cancers and represents the second cause of death in the world, we performed the study in NCI-N87 gastric cancer cell line. The effect of the drug resulted in the inhibition of cell proliferation, including a reduction of cell number and viability, in the decrease of MIB-1 proliferative index as well as in the upregulation of cyclin-dependent kinase inhibitor 1A and 1B (CDKN1A and CDKN1B), and growth arrest and DNA-damage 45A (GADD45A) genes. The cytotoxicity was apoptotic as shown by FACS analysis. Additionally, gentamicin reduced HER2 protein, indicating a minor tumor aggressiveness. To further define the involvement of sphingomyelin metabolism in the response to the drug, gene and protein expression of acid and neutral sphingomeylinase was analyzed in comparison with phosphatase and tensin homolog deleted on chromosome 10 (PTEN) and vitamin D receptor (VDR), molecules involved in cancer. Gentamicin induced a downregulation of PTEN, VDR, and neutral sphingomyelinase and a strong upregulation of acid sphingomyelinase. Of note, we identified the same upregulation of acid sphingomyelinase upon gentamicin treatment in other cancer cells and not in normal cells. These findings provide new insights into acid sphingomyelinase as therapeutic target, reinforcing studies on the potential role of gentamicin in anticancer therapy. Full article
(This article belongs to the Special Issue Lipid as a Cancer Therapeutic Target)
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Open AccessArticle
Expression of Autotaxin–Lysophosphatidate Signaling-Related Proteins in Breast Cancer with Adipose Stroma
Int. J. Mol. Sci. 2019, 20(9), 2102; https://doi.org/10.3390/ijms20092102 - 29 Apr 2019
Abstract
This research aimed to evaluate the expression and clinical implication of autotaxin (ATX)-lysophosphatidate (LPA) signaling-related proteins in breast cancer with adipose stroma. To this end, a tissue microarray (TMA) was constructed from 137 breast cancer tissues with adipose stroma and 329 breast cancer [...] Read more.
This research aimed to evaluate the expression and clinical implication of autotaxin (ATX)-lysophosphatidate (LPA) signaling-related proteins in breast cancer with adipose stroma. To this end, a tissue microarray (TMA) was constructed from 137 breast cancer tissues with adipose stroma and 329 breast cancer tissues with non-adipose stroma (inflammatory stroma: n = 81, 24.6%; fibrous stroma: n = 246, 75.4%). Immunohistochemical staining for ATX-LPA signaling-related proteins (ATX, LPA1, LPA2, and LPA3) was performed on the TMA. The results showed that LPA2 in tumor cells and LPA3 in stromal cells were highly expressed in breast cancer with adipose stroma and breast cancer with adipose and inflammatory stroma, respectively. Stromal LPA1 positivity (p = 0.017) and stromal LPA3 positivity (p = 0.004) were higher in breast cancer with adipose stroma containing CD68-positive crown-like structures (CLS). Stromal ATX positivity (p = 0.010) and stromal LPA3 positivity (p = 0.009) were higher in breast cancer with adipose tissue containing CD163-positive CLS. In breast cancer with adipose stroma, the number of CD163-positive macrophages was greater with stromal ATX positivity (p = 0.003), and the number of CD68-positive and CD163-positive macrophages were greater in cases with stromal LPA3 positivity. In conclusion, ATX-LPA signaling-related proteins are highly expressed in breast cancer with adipose stroma, with associated macrophage infiltration. Full article
(This article belongs to the Special Issue Lipid as a Cancer Therapeutic Target)
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Review

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Open AccessReview
PI3K/mTOR Pathway Inhibition: Opportunities in Oncology and Rare Genetic Diseases
Int. J. Mol. Sci. 2019, 20(22), 5792; https://doi.org/10.3390/ijms20225792 - 18 Nov 2019
Abstract
The phosphatidylinositol 3-kinase (PI3K)/mammalian target of rapamycin (mTOR) signaling pathway has been implicated as a cancer target. Big pharma players and small companies have been developing small molecule inhibitors of PI3K and/or mTOR since the 1990s. Although four inhibitors have been approved, many [...] Read more.
The phosphatidylinositol 3-kinase (PI3K)/mammalian target of rapamycin (mTOR) signaling pathway has been implicated as a cancer target. Big pharma players and small companies have been developing small molecule inhibitors of PI3K and/or mTOR since the 1990s. Although four inhibitors have been approved, many open questions regarding tolerability, patient selection, sensitivity markers, development of resistances, and toxicological challenges still need to be addressed. Besides clear oncological indications, PI3K and mTOR inhibitors have been suggested for treating a plethora of different diseases. In particular, genetically induced PI3K/mTOR pathway activation causes rare disorders, known as overgrowth syndromes, like PTEN (phosphatase and tensin homolog) hamartomas, tuberous sclerosis complex (TSC), phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha (PIK3CA)-related overgrowth spectrum (PROS), and activated PI3-Kinase delta syndrome (PI3KCD, APDS). Some of those disorders likeTSC or hemimegalencephaly, which are one of the PROS disorders, also belong to a group of diseases called mTORopathies. This group of syndromes presents with additional neurological manifestations associated with epilepsy and other neuropsychiatric symptoms induced by neuronal mTOR pathway hyperactivation. While PI3K and mTOR inhibitors have been and still are intensively tested in oncology indications, their use in genetically defined syndromes and mTORopathies appear to be promising avenues for a pharmacological intervention. Full article
(This article belongs to the Special Issue Lipid as a Cancer Therapeutic Target)
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Open AccessReview
Targeting Long Chain Acyl-CoA Synthetases for Cancer Therapy
Int. J. Mol. Sci. 2019, 20(15), 3624; https://doi.org/10.3390/ijms20153624 - 24 Jul 2019
Cited by 1
Abstract
The deregulation of cancer cell metabolic networks is now recognized as one of the hallmarks of cancer. Abnormal lipid synthesis and extracellular lipid uptake are advantageous modifications fueling the needs of uncontrolled cancer cell proliferation. Fatty acids are placed at the crossroads of [...] Read more.
The deregulation of cancer cell metabolic networks is now recognized as one of the hallmarks of cancer. Abnormal lipid synthesis and extracellular lipid uptake are advantageous modifications fueling the needs of uncontrolled cancer cell proliferation. Fatty acids are placed at the crossroads of anabolic and catabolic pathways, as they are implicated in the synthesis of phospholipids and triacylglycerols, or they can undergo β-oxidation. Key players to these decisions are the long-chain acyl-CoA synthetases, which are enzymes that catalyze the activation of long-chain fatty acids of 12–22 carbons. Importantly, the long-chain acyl-CoA synthetases are deregulated in many types of tumors, providing a rationale for anti-tumor therapeutic opportunities. The purpose of this review is to summarize the last up-to-date findings regarding their role in cancer, and to discuss the related emerging tumor targeting opportunities. Full article
(This article belongs to the Special Issue Lipid as a Cancer Therapeutic Target)
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Open AccessReview
Sphingolipid-Transporting Proteins as Cancer Therapeutic Targets
Int. J. Mol. Sci. 2019, 20(14), 3554; https://doi.org/10.3390/ijms20143554 - 20 Jul 2019
Abstract
The understanding of the role of sphingolipid metabolism in cancer has tremendously increased in the past ten years. Many tumors are characterized by imbalances in sphingolipid metabolism. In many cases, disorders of sphingolipid metabolism are also likely to cause or at least promote [...] Read more.
The understanding of the role of sphingolipid metabolism in cancer has tremendously increased in the past ten years. Many tumors are characterized by imbalances in sphingolipid metabolism. In many cases, disorders of sphingolipid metabolism are also likely to cause or at least promote cancer. In this review, sphingolipid transport proteins and the processes catalyzed by them are regarded as essential components of sphingolipid metabolism. There is much to suggest that these processes are often rate-limiting steps for metabolism of individual sphingolipid species and thus represent potential target structures for pharmaceutical anticancer research. Here, we summarize empirical and biochemical data on different proteins with key roles in sphingolipid transport and their potential role in cancer. Full article
(This article belongs to the Special Issue Lipid as a Cancer Therapeutic Target)
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