Next Article in Journal
Epidermal Growth Factor Receptor in Pancreatic Cancer
Next Article in Special Issue
The Role of Nrf2 and Cytoprotection in Regulating Chemotherapy Resistance of Human Leukemia Cells
Previous Article in Journal / Special Issue
Role of Methionine Adenosyltransferase Genes in Hepatocarcinogenesis

Cancers 2011, 3(2), 1498-1512; https://doi.org/10.3390/cancers3021498

Review
To Die or to Survive, a Fatal Question for the Destiny of Prostate Cancer Cells after Androgen Deprivation Therapy
1
The Vancouver Prostate Centre, 2660 Oak St., Vancouver, BC V6H 3Z6, Canada
2
Department of Urologic Sciences, University of British Columbia, Vancouver, BC V6H 3Z6, Canada
3
Department of Surgery and Brain Research Centre, University of British Columbia, Vancouver, BC V6H 3Z6, Canada
*
Author to whom correspondence should be addressed.
Received: 4 February 2011; in revised form: 16 March 2011 / Accepted: 17 March 2011 / Published: 24 March 2011

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 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majority of cancers progress to a castration-resistant/androgen-independent state where the cell death processes are no longer active.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.
Keywords:
prostate cancer; cell death mechanisms; apoptosis; progression; castration resistance

1. Introduction

Prostate cancer is the most commonly diagnosed non-skin cancer in men and one of the leading causes of cancer-death [1]. It has been estimated that there will be almost 217,730 newly diagnosed prostate cancer cases and 32,050 of them will die of the disease this year in the United States. While frequently curable in its early stages by surgery or radiotherapy, many patients will either have a later recurrence or initially present with locally advanced or metastatic disease [2,3]. The primary treatment for advanced metastatic prostate cancer is androgen deprivation therapy (ADT). In both normal and neoplastic prostates, the male sex hormones, termed androgens, play critical roles in cell growth and survival [4]. Androgen-mediated mitogenic and survival signaling are transduced through a protein called the androgen receptor (AR), which functions as an androgen-activated transcription factor to regulate specific genes. The reliance of prostate cancer cells on androgens provides the basis for using ADT as the first line treatment for advanced prostate cancer. ADT may be achieved through surgical (i.e., removal of the testes) or medical castration. The latter is usually achieved by administration of either LH-RH agonists or antagonists, which cause an inhibition of testicular androgen production. ADT may also involve combining castration with anti-androgen therapy, where steroidal or nonsteroidal AR antagonists are given to block androgen-mediated growth and survival signaling through direct competition with androgens for binding to the AR [5-7]. After ADT, cell death occurs causing involution of normal prostate glandular epithelia and regression of androgen-dependent prostate cancer cells [8]. While apoptosis is generally believed to be the primary mechanism for programmed cell death in prostate cancers, other forms of cell death may also be involved and are also discussed in this review.

2. Cellular Mechanisms for Cell Death

2.1. Apoptosis

At least four major cell death modalities (apoptosis, autophagy, necrosis and necroptosis) have been described [9-11]. Apoptosis, considered type 1 cell death, is caused by either polymerizations of death receptors such as FAS and TNF-R1 by extrinsic FAS ligand or TNF-α binding, or elicited by intrinsic signals that induce mitochondria to release cytochrome C, which acts as a potent catalyst for apoptosis. Members of the Bcl-2 super family of proteins have distinct activities, either pro-apoptotic (Bax, Bak, Bid, Bim) or anti-apoptotic (Bcl-2, Bcl-XL, Bcl-W), which regulate the apoptotic process by controlling the mitochondrial death signaling through cytochrome C release [11-13]. The redundancy of key molecules to control apoptosis may cross regulate with and compensate for each other. In both extrinsic and intrinsic signaling-mediated apoptosis, cleavage-activation of an array of intracellular proteases within cells, called caspases, leads to execution of the cell death program [14]. Morphologically, apoptosis is defined by nuclear pyknosis (chromatin condensation) and karyorhexis (nuclear fragmentation). Progressive cellular condensation and budding form apoptotic bodies surrounded by membranes and contain intact cytoplasmic organelles or fragments of the nucleus [11,13]. These apoptotic bodies are eventually engulfed by resident phagocytes. Apoptosis is involved in tissue homeostasis, embryonic development, and disease initiation and progression.

2.2. Autophagic Cell Death

While apoptosis may induce rapid destruction of all cell structures and organelles, type 2 cell death, referred to as autophagic cell death, involves a rather slow process [11]. Upon nutrient deprivation, growth factor withdrawal or other stressors, autophagosomes, which are double-membrane vacuoles, are formed in eukaryotic cells [11]. Autophagosomes sequester cytoplasmic proteins, mitochondria, endoplasmic reticulum, and ribosomes for eventual degradation by lysosomal hydrolases. This “self-eating” process called autophagy is a means of disposing of defective organelles and macromolecular structures, as well as damaged and aggregate-prone proteins. Autophagy has been shown to be involved in normal tissue remodeling, embryogenesis, in counteracting age-related physiologic changes, and in foreign antigen presentation to the immune system [11,15,16]. However, aberrant regulation of autophagy has also been associated with development of pathologies such as neurodegenerative disease and carcinogenesis. Massive autophagic vacuolization has been observed in some instances of cell death. [11,15,17,18]

2.3. Necrosis

In both type 1 and type 2 cell death, the remains of cells are disposed of by phagocytosis without an inflammatory response. This is in contrast to necrosis, the type 3 cell death, in which nonspecific and non-physiological stress, such as osmotic lysis, may induce diffusion of lytic enzymes and eventually cause cell destruction and a strong inflammation response. Morphologically, necrosis is characterized by an enlarged cell body (oncosis) that finally culminates in rupture of the plasma membrane and the dismantling of swollen organelles [9,11,19].

2.4. Necroptosis

While necrosis has been considered non-programmable and unregulated, another form of programmed cell death, necroptosis, has been characterized in recent years [19,20]. It is a special type of cell necrosis initiated by engagement of death receptors (TNF-R1) and requires the kinase activity of receptor-interacting protein 1 (RIP1; also known as RIPK1) and RIP3 (also known as RIPK3) [19,20]. In contrast to necrosis, necroptosis can be regulated by genetic, epigenetic, and pharmacological factors [20]. For example, pharmacological or genetic inactivation of caspases can cause cells to exhibit morphologies with either mixed necrotic and apoptotic features or complete necrosis [19]. Necroptosis participates in the pathogenesis of many diseases, including ischemic injury, neuro-degeneration and viral infection. Like necrosis, necroptosis has been considered harmful to the body because massive cellular disintegration may promote severe local inflammation which may, in turn, support tumor growth [21].

3. Cell Death Processes Activated in Prostate Cancers after ADT

While apoptosis has been well documented as a primary mechanism for prostate tumor regression after ADT, it is likely not the only type of cell death mechanism involved. Upon androgen withdrawal, autophagosomes, the hallmark of autophagy, have been observed in human prostate cancer cell lines [22,23]. Autophagy has been reported to have a protective role in prostate cancer cells but it may also induce autophagic cell death [9,22]. Since androgens have been reported to regulate blood flow to the prostate [24], ADT may lead to decreased blood flow to the prostate, resulting in a hypoxic environment with accompanying apoptosis of capillary endothelial cells in the tumor bed [24-26]. The apoptotic pathways in prostate cancer cells may subsequently be blocked by increased expression of hypoxia-inducible factor I (HIF-1) and this anoxic stress, induced by ADT, may render the cells unable to initiate an apoptotic cascade. The apoptotic process may then be eventually supplanted by necrosis, probably with necroptosis as the intermittent process. Hence different modalities of cell death including apoptosis, autophagy, necroptosis and necrosis may be induced by ADT, making it an effective therapy to treat locally advanced and metastatic androgen-dependent prostate cancers. However, prostate cancer cells eventually progress to an androgen-independent (AI) or castration-resistant state where conventional ADT is ineffective. When this occurs, the median survival of the patient decreases to ∼16–18 months [2,27,28]. Thus, a major obstacle for successfully treating prostate cancer and prolonging survival is progression to castration resistance with its attendant failure to activate cell death mechanisms.

While activation of apoptosis is considered beneficial for treating prostate cancer, activation of autophagy can have the opposite effect. Indeed, suppression of the autophagic process pharmacologically or by knocking down Beclin 1, a molecule that is known to be necessary for autophagy and to regulate autophagic initiation by forming a complex with PI3K, results in increased apoptosis. Autophagy may serve to protect the cells from ADT induced cell apoptosis and thereby promote castration resistant prostate cancer (CRPC). If cells survive metabolic, genotoxic or anoxic stress, their capacity to initiate further apoptotic cascades may be blocked by endogenous inhibitors, including high concentrations of anti-apoptotic molecules such as hypoxia HIF-1 and Bcl-2, or through down regulation of pro-apoptotic molecules like Bad. As mentioned above, under these conditions apoptosis may be replaced by necrosis. While necrosis can result in shrinkage of the tumor, massive cellular disintegration may also promote severe local inflammation and support tumor growth [21]. The hazardous effects of the apoptotic to necrotic conversion with accompanying release of necrotic mediators that may promote cancer progression is supported by clinical observations in which the presence of necrosis is almost always correlated with poor prognosis. High-mobility group box1 protein (HMGB1) for example, is one such mediator which is released by necrotic but not apoptotic cells. Recently, HMGB1 has been shown to be secreted from prostate cancer cells and its over-expression is associated with prostate cancer progression [13,17].Though HMGB1 can regulate gene expression, it acts primarily as a cytokine to promote angiogenesis and extravascular migration of inflammatory cells. This initiates inflammatory reactions which may promote cancer growth [4,34]. Accordingly, necrosis may also be induced after ADT and signals released from necrotic cells such as HMGB1 may be important mediators for promoting the emergence of CRPC. Interestingly, HMGB1 itself is critical for the survival of cancer cells since knockdown of HMGB1 results in a caspase-3-dependent apoptosis [29]. In conclusion, it is thus conceivable that in order to make ADT more effective, suppression of autophagy, which is protective against cells death, and blocking survival signals mediated through necroptosis or necrosis may be necessary.

4. Mechanisms Underlying Progression of Prostate Cancers to Castration Resistance

4.1. Persistence of Active AR is Pivotal to the Progression of CRPC

Acquisition of the capacity for growth self-sufficiency and the evasion of cell death processes are considered to be critical hallmarks for the malignant progression of cancers [12]. In the majority of prostate cancers, formerly androgen-dependent cells acquire the ability to grow in an androgen-deprived environment and to evade apoptosis and other cell death processes which were previously active. We and others have shown that the AR remains active in most castration resistant prostate cancers (CRPCs) and that knocking down the AR in CRPC model systems can often cause complete regression of these tumors [30-32]. Amplification of the AR gene and over-expression of AR have also been observed in CRPC [33-36]. High levels of nuclear AR are found in most locally advanced CRPCs and in bone metastases. This is further supported by increased AR mRNA levels consistently observed with the progression to CRPC in gene microarray studies [30]. Overexpressed AR may thus enable cancer cells to respond to low levels of androgen and to transduce signals sufficient for cell growth and survival.

4.2. AR Mutations

AI growth and survival in CRPC can also be maintained by constitutively active mutant ARs [37,38]. The incidence of somatic mutation in the AR in prostate cancer samples occurs more frequently in tumor cells of distant metastases and recurrent prostate cancer following ADT compared to that seen in primary prostate cancers. Mutations in the AR may impart altered sensitivity and specificity. For example, point mutations in the AR gene identified in metastatic cells from patients and from AI prostate-cancer cell lines could be activated by progesterone and estrogen [37]. An AR gene harboring a gain-of-function mutation which is constitutively active can thus render prostate cancer cells independent of androgen and with a castration-resistant phenotype [37,38]. Moreover, in recent years, constitutively active AR splice variants lacking the ligand binding domain have been identified in AI prostate cancer cell lines and tissues, with the highest levels observed in late stage CRPC [39-44]. Targeting the ligand binding domain with anti-androgens or selective siRNA silencing of full length AR blocked the cell growth-promoting effects of constitutively active AR variants, indicating that the gain-of-function of such constitutively active AR splice variants still requires the full-length AR [40]. However, the fact that such AR variants are capable of conferring anchorage-independent growth in vitro and CRPC growth in vivo [40,43] and that they can regulate the expression of full-length AR and modulate AR activity [39,44] suggests their important roles for the progression of CRPC.

4.3. AR Coregulators

AR modulates transcription of androgen-responsive genes via recruitment of coregulators that influence a number of functional properties of the receptors, including ligand selectivity and DNA binding capacity [45-48]. There exist four main types of coregulators for AR: (1) molecular chaperones that coordinate AR maturation and movement, (2) histone modifiers, (3) coordinators of transcription and (4) DNA structural modifiers. Functionally, co-regulators interact with AR to either promote (co-activator) or inhibit (co-repressor) AR activity. While AR activity may be promoted when coactivator levels increase, it has been demonstrated that AR recruitment of corepressors is a key mediator of antagonist mediated inhibition of steroid receptors, suggesting that loss of corepressor expression and the subsequent release of the suppression of AR activity may facilitate the progression to CRPC [48].

4.4. Crosstalk of AR with other Cell Signaling Pathways

There are at least four prominent signaling pathways through which AR crosstalk may contribute to castration resistance: (i) the PI3K/Akt pathway, (ii) receptor tyrosine kinases, (iii) the p38 MAPK pathway, and (iv) the Wnt/β-catenin pathway.

4.4.1. AR crosstalk with PI3K/Akt Pathway

Perhaps the most important pathway activated in CRPC progression is the phosphatidylinositol 3-kinase (PI3K)/Akt pathway. Overexpression of insulin-like growth factor 1 receptor (IGF-1R) has been observed in many prostate cancers and, in particular, it is upregulated in vivo during the progression to castration resistance [49,50]. Signaling through the upregulated IGF-1R results in enhanced autophosphorylation and tyrosine phosphorylation of IGF-IR substrates, which enables the recruitment of different effectors to induce potent activation of the PI3K/Akt pathway [51]. Activation of PI3K leads to phospho-activation of Akt and subsequent inhibitory phosphorylation of the pro-apoptotic molecule, Bad. Consequently, the anti-apoptotic capacity is amplified within the cancer cells [49,50,52]. In addition, loss of PTEN, a tumor suppressor gene encoding a phosphatase to suppress PI3K, provides another very important mechanism for progression to CRPC. Indeed, PTEN function is lost by gene deletion or mutation in more than 60% of prostate cancers, notably those with high Gleason scores and advanced pathological stage. By eliminating its negative regulation function, loss of PTEN will lead to activation of the PI3K/Akt pathway and activation of the anti-apoptotic signaling as mentioned above [53-56]. Direct evidence that loss of PTEN regulates cell survival is based on the observation that ectopic expression of PTEN in prostate cancer cells suppresses transcription of the anti-apoptotic molecule Bcl-2 via the cAMP response element-binding protein (CREB). Accordingly, loss of PTEN abrogates CREB-mediated suppression of Bcl-2 and thus may contribute to increased Bcl-2 levels in advanced CRPC [57]. Indeed, more than 80% of prostate cancer samples with increased Bcl-2 expression were also found to have a loss of PTEN. In addition to the anti-apoptotic or survival signals mediated through activated PI3K, signaling through activated PI3K regulates AR activities by inducing AR phosphorylation, altering AR transcription, and promoting AR translocation into the nucleus [58-60], all of which may contribute to progression to CRPC.

4.4.2. AR Crosstalk with Receptor Tyrosine Kinases

Overexpression and amplification of human epidermal growth factor 2 (HER-2) occur in many cancers and are associated with poor prognosis [61-64]. Though it is well accepted that the HER-2 gene is not often amplified in primary prostate cancers [62,64-68], our observations together with others have demonstrated that overexpression of HER-2 proteins is associated with CRPC progression [62,69]. HER-2 forms heterodimers with other EGFR family members and these complexes become hypersensitive to activation by various ligands such as EGF, TGFα, neuregulins, etc [65,70]. Ligand binding to HER-2 initiates signaling cascades leading to potent activation of Ras/Raf/MAPK, which results in increased cell proliferation and decreased cell death [70-72]. Importantly, over-expressed HER-2 can dimerize with ERBB3 to transduce signals for stabilizing AR protein levels and optimize binding of AR to promoter/enhancer regions of androgen-regulated genes, thereby promoting AR activities [73]. Hence, overexpressed HER-2 is capable of conferring AI growth both in vitro and in vivo and promoting CRPC progression [61,72].

4.4.3. AR Crosstalk with the p38 MAPK Pathway

Activation of the p38 MAPK pathway may be another mechanism for progression to CRPC. This is particularly true when prostate cancer cells are in a hypoxic environment. Many solid tumors have hypoxic regions which are associated with disease progression and treatment resistance [23]. Since androgens have been reported to be able to regulate blood flow to the prostate [24], ADT will lead to decreased blood flow resulting in a hypoxic environment and subsequent apoptosis of capillary endothelial cells [24-26]. Upon induction of hypoxia, p38 MAPK is activated and phosphorylates HSP27 which can then translocate into the nucleus to stabilize AR [74].

4.4.4. AR Crosstalk with the Wnt/β-catenin Pathway

There are two types of Wnt/β-catenin signaling pathways: the canonical and non-canonical. In the canonical pathway, Wnt ligands bind members of the Frizzled family transmembrane receptors resulting in the stabilization of β-catenin, which translocates into the nucleus to form a transcriptional complex with T-cell factor (Tcf) and lymphoid enhancer factor (LEF) [75]. Expression of genes involved in cell proliferation and apoptosis, such as c-myc, AP-1 members, c-jun and fra-1 and cyclin D1, are subsequently initiated by this complex. In addition, β-catenin is able to promote AR activity by directly interacting with AR. Physically, β-catenin binds to the ligand binding domain (LBD) and N-terminus of the AR via the first six armadillo repeats and this interaction enhances AR-mediated transcription [76-79]. Deregulation of the Wnt/β-catenin pathway in advanced CRPC has been noted by many investigators [80-83]. Members of the canonical Wnt pathway, including Wnt-3a and Wnt-1 and β-catenin, have been shown to be up-regulated in metastatic prostate cancer and β-catenin and AR have been shown to co-localize in the nucleus in advanced prostate cancer samples. Interestingly, upon activation with a canonical Wnt ligand, AR can activate transcription of androgen responsive genes (e.g., PSA) in the absence of androgen and thereby support AI cell growth. This process is associated with formation of AR-β-catenin complexes at the PSA promoter in the nucleus [84,85]. At castration levels of androgen, unbound AR was also found to be recruited to TCF/LEF/β-catenin-regulated promoters of genes such as myc and cyclin D1 which are critical for cell growth and survival [85]. Expression of those genes may promote progression to CRPC.

4.5. De Novo Synthesis of Androgen

In most cases of CRPC, tumors resume their expression of multiple AR-regulated genes such as PSA, TMPRSS2:ERG fusion genes, etc [86,87], indicating the reactivation of AR. As discussed previously, elevated expression levels of AR, AR mutations that transduce weak androgen signals, high levels of constitutively active AR splice variants lacking ligand binding and increased expression of transcriptional coactivator proteins may contribute to the reactivation of AR. In addition, it has been observed that intraprostatic levels of androgens remain moderately high in CRPC, which is the result of de novo synthesis of testosterone and DHT from weak adrenal androgens or from cholesterol within CRPC cells [87-89]. The reactivation of AR by such de novo synthesized androgen may be another molecular mechanism for the progression of CRPC.

In conclusion, hyperactive AR signaling by any of the mechanisms discussed above is linked to cell survival and the progression of CRPC.

4.6. Prostate Cancer Stem/Progenitor Cells

It is believed that there may exist prostate cancer stem/progenitor cells which may arise from normal tissue stem cells [90]. These prostate cancer stem/progenitor cells are likely AR negative [90,91]. As discussed previously, ADT has been designed to eradicate cancer cells within a tumor by targeting the AR positive population. However, by eradicating androgen-dependent prostate cancer cells, ADT may actually promote disease progression by activating normally quiescent cancer stem cells to repopulate the tumor with AR negative, androgen-independent cells [90-92]. Although unproven, the repopulation of the prostate tumor with androgen-independent cancer cells may be a very important mechanism in progression to CRPC.

5. Conclusions

Cells die in at least four distinct manners including apoptosis, autophagy, necrosis and necroptosis. Extrinsic or intrinsic stimuli such as DNA damage, loss of cell cycle control, hypoxia and withdrawal of growth factors as well as numerous chemo- or radio- therapies may cause cells to die in one or more of these cell death modalities. As the most widely used therapy for locally advanced and/or metastatic prostate cancers, ADT has proven to be effective in inducing extensive cell death of cancer cells. However, prostate cancers progress to become refractory to castration-induced cell death. While epigenetic modulation or genetic mutation in the AR play important roles in CRPC progression, the persistence of a functional AR is also critical. The AR can function as an interface to crosstalk with various signaling pathways to provide signals sufficient enough for cell proliferation and survival in the absence of androgen. Hence, targeting the AR as well as downstream signaling molecules critical for progression to castration resistance may provide effective therapies to treat CRPC and increase patient survival.

Acknowledgments

The authors wish to acknowledge financial support provided by the Canadian Institutes for Health Research (CIHR) and the S.T.A.R. Project from the Prostate Cancer Canada (with the support of Safeway Canada).

Reference

  1. Jemal, A.; Siegel, R.; Xu, J.; Ward, E. Cancer statistics, 2010. CA Cancer J. Clin. 2010, 60, 277–300. [Google Scholar]
  2. Albertsen, P.C.; Hanley, J.A.; Fine, J. 20-year outcomes following conservative management of clinically localized prostate cancer. JAMA 2005, 293, 2095–2101. [Google Scholar]
  3. Fleshner, N. Defining high-risk prostate cancer: Current status. Can. J. Urol. 2005, 12, 14–17, discussion 94-96. [Google Scholar]
  4. Berchem, G.J.; Bosseler, M.; Sugars, L.Y.; Voeller, H.J.; Zeitlin, S.; Gelmann, E.P. Androgens induce resistance to Bcl-2-mediated apoptosis in lncap prostate cancer cells. Cancer Res. 1995, 55, 735–738. [Google Scholar]
  5. Miyamoto, H.; Messing, E.M.; Chang, C. Androgen deprivation therapy for prostate cancer: Current status and future prospects. Prostate 2004, 61, 332–353. [Google Scholar]
  6. Fair, W.R.; Aprikian, A.G.; Cohen, D.; Sogani, P.; Reuter, V. Use of neoadjuvant androgen deprivation therapy in clinically localized prostate cancer. Clin. Invest. Med. 1993, 16, 516–522. [Google Scholar]
  7. Quon, H.; Loblaw, D.A. Androgen deprivation therapy for prostate cancer-review of indications in 2010. Curr. Oncol. 2010, 17 (Suppl. 2), S38–S44. [Google Scholar]
  8. Denmeade, S.R.; Lin, X.S.; Isaacs, J.T. Role of programmed (apoptotic) cell death during the progression and therapy for prostate cancer. Prostate 1996, 28, 251–265. [Google Scholar]
  9. Galluzzi, L.; Maiuri, M.C.; Vitale, I.; Zischka, H.; Castedo, M.; Zitvogel, L.; Kroemer, G. Cell death modalities: Classification and pathophysiological implications. Cell Death Differ. 2007, 14, 1237–1243. [Google Scholar]
  10. Kroemer, G.; Galluzzi, L.; Vandenabeele, P.; Abrams, J.; Alnemri, E.S.; Baehrecke, E.H.; Blagosklonny, M.V.; El-Deiry, W.S.; Golstein, P.; Green, D.R.; Hengartner, M.; Knight, R.A.; Kumar, S.; Lipton, S.A.; Malorni, W.; Nunez, G.; Peter, M.E.; Tschopp, J.; Yuan, J.; Piacentini, M.; Zhivotovsky, B.; Melino, G. Classification of cell death: Recommendations of the nomenclature committee on cell death 2009. Cell Death Differ. 2009, 16, 3–11. [Google Scholar]
  11. Stepien, A.; Izdebska, M.; Grzanka, A. The types of cell death. Postepy Hig. Med. Dosw. (Online) 2007, 61, 420–428. [Google Scholar]
  12. Hanahan, D.; Weinberg, R.A. The hallmarks of cancer. Cell 2000, 100, 57–70. [Google Scholar]
  13. Wyllie, A.H.; Kerr, J.F.; Currie, A.R. Cell death: The significance of apoptosis. Int. Rev. Cytol. 1980, 68, 251–306. [Google Scholar]
  14. Thornberry, N.A. Caspases: Key mediators of apoptosis. Chem. Biol. 1998, 5, R97–103. [Google Scholar]
  15. Singletary, K.; Milner, J. Diet, autophagy, and cancer: A review. Cancer Epidemiol. Biomarkers Prev. 2008, 17, 1596–1610. [Google Scholar]
  16. Chen, N.; Karantza-Wadsworth, V. Role and regulation of autophagy in cancer. Biochim. Biophys. Acta 2009, 1793, 1516–1523. [Google Scholar]
  17. Karantza-Wadsworth, V.; White, E. Role of autophagy in breast cancer. Autophagy 2007, 3, 610–613. [Google Scholar]
  18. Jin, S.; White, E. Role of autophagy in cancer: Management of metabolic stress. Autophagy 2007, 3, 28–31. [Google Scholar]
  19. Galluzzi, L.; Kroemer, G. Necroptosis: A specialized pathway of programmed necrosis. Cell 2008, 135, 1161–1163. [Google Scholar]
  20. Vandenabeele, P.; Galluzzi, L.; Vanden Berghe, T.; Kroemer, G. Molecular mechanisms of necroptosis: An ordered cellular explosion. Nat. Rev. Mol. Cell Biol. 2010, 11, 700–714. [Google Scholar]
  21. Vakkila, J.; Lotze, M.T. Inflammation and necrosis promote tumour growth. Nat. Rev. Immunol. 2004, 4, 641–648. [Google Scholar]
  22. Li, M.; Jiang, X.; Liu, D.; Na, Y.; Gao, G.F.; Xi, Z. Autophagy protects lncap cells under androgen deprivation conditions. Autophagy 2008, 4, 54–60. [Google Scholar]
  23. Marignol, L.; Coffey, M.; Lawler, M.; Hollywood, D. Hypoxia in prostate cancer: A powerful shield against tumour destruction? Cancer Treat. Rev. 2008, 34, 313–327. [Google Scholar]
  24. Anastasiadis, A.G.; Stisser, B.C.; Ghafar, M.A.; Burchardt, M.; Buttyan, R. Tumor hypoxia and the progression of prostate cancer. Curr. Urol. Rep. 2002, 3, 222–228. [Google Scholar]
  25. Shabisgh, A.; Tanji, N.; D'Agati, V.; Burchardt, M.; Rubin, M.; Goluboff, E.T.; Heitjan, D.; Kiss, A.; Buttyan, R. Early effects of castration on the vascular system of the rat ventral prostate gland. Endocrinology 1999, 140, 1920–1926. [Google Scholar]
  26. Buttyan, R.; Ghafar, M.A.; Shabsigh, A. The effects of androgen deprivation on the prostate gland: Cell death mediated by vascular regression. Curr. Opin. Urol. 2000, 10, 415–420. [Google Scholar]
  27. Kent, E.C.; Hussain, M.H. The patient with hormone-refractory prostate cancer: Determining who, when, and how to treat. Urology 2003, 62, 134–140. [Google Scholar]
  28. Martel, C.L.; Gumerlock, P.H.; Meyers, F.J.; Lara, P.N. Current strategies in the management of hormone refractory prostate cancer. Cancer Treat. Rev. 2003, 29, 171–187. [Google Scholar]
  29. Gnanasekar, M.; Thirugnanam, S.; Ramaswamy, K. Short hairpin RNA (shRNA) constructs targeting high mobility group box-1 (hmgb1) expression leads to inhibition of prostate cancer cell survival and apoptosis. Int. J. Oncol. 2009, 34, 425–431. [Google Scholar]
  30. Chen, C.D.; Welsbie, D.S.; Tran, C.; Baek, S.H.; Chen, R.; Vessella, R.; Rosenfeld, M.G.; Sawyers, C.L. Molecular determinants of resistance to antiandrogen therapy. Nat. Med. 2004, 10, 33–39. [Google Scholar]
  31. Cheng, H.; Snoek, R.; Ghaidi, F.; Cox, M.E.; Rennie, P.S. Short hairpin RNA knockdown of the androgen receptor attenuates ligand-independent activation and delays tumor progression. Cancer Res. 2006, 66, 10613–10620. [Google Scholar]
  32. Snoek, R.; Cheng, H.; Margiotti, K.; Wafa, L.A.; Wong, C.A.; Wong, E.C.; Fazli, L.; Nelson, C.C.; Gleave, M.E.; Rennie, P.S. In vivo knockdown of the androgen receptor results in growth inhibition and regression of well-established, castration-resistant prostate tumors. Clin. Cancer Res. 2009, 15, 39–47. [Google Scholar]
  33. Koivisto, P.; Visakorpi, T.; Kallioniemi, O.P. Androgen receptor gene amplification: A novel molecular mechanism for endocrine therapy resistance in human prostate cancer. Scand. J. Clin. Lab. Invest. Suppl. 1996, 226, 57–63. [Google Scholar]
  34. Brown, R.S.; Edwards, J.; Dogan, A.; Payne, H.; Harland, S.J.; Bartlett, J.M.; Masters, J.R. Amplification of the androgen receptor gene in bone metastases from hormone-refractory prostate cancer. J. Pathol. 2002, 198, 237–244. [Google Scholar]
  35. Edwards, J.; Krishna, N.S.; Grigor, K.M.; Bartlett, J.M. Androgen receptor gene amplification and protein expression in hormone refractory prostate cancer. Br. J. Cancer 2003, 89, 552–556. [Google Scholar]
  36. Golias, C.; Iliadis, I.; Peschos, D.; Charalabopoulos, K. Amplification and co-regulators of androgen receptor gene in prostate cancer. Exp. Oncol. 2009, 31, 3–8. [Google Scholar]
  37. Taplin, M.E.; Bubley, G.J.; Shuster, T.D.; Frantz, M.E.; Spooner, A.E.; Ogata, G.K.; Keer, H.N.; Balk, S.P. Mutation of the androgen-receptor gene in metastatic androgen-independent prostate cancer. N. Engl. J. Med. 1995, 332, 1393–1398. [Google Scholar]
  38. Suzuki, H.; Akakura, K.; Komiya, A.; Aida, S.; Akimoto, S.; Shimazaki, J. Codon 877 mutation in the androgen receptor gene in advanced prostate cancer: Relation to antiandrogen withdrawal syndrome. Prostate 1996, 29, 153–158. [Google Scholar]
  39. Sun, S.; Sprenger, C.C.; Vessella, R.L.; Haugk, K.; Soriano, K.; Mostaghel, E.A.; Page, S.T.; Coleman, I.M.; Nguyen, H.M.; Sun, H.; Nelson, P.S.; Plymate, S.R. Castration resistance in human prostate cancer is conferred by a frequently occurring androgen receptor splice variant. J. Clin. Invest. 2010, 120, 2715–2730. [Google Scholar]
  40. Watson, P.A.; Chen, Y.F.; Balbas, M.D.; Wongvipat, J.; Socci, N.D.; Viale, A.; Kim, K.; Sawyers, C.L. Constitutively active androgen receptor splice variants expressed in castration-resistant prostate cancer require full-length androgen receptor. Proc. Natl. Acad. Sci. USA 2010, 107, 16759–16765. [Google Scholar]
  41. Marcias, G.; Erdmann, E.; Lapouge, G.; Siebert, C.; Barthelemy, P.; Duclos, B.; Bergerat, J.P.; Ceraline, J.; Kurtz, J.E. Identification of novel truncated androgen receptor (ar) mutants including unreported pre-mRNA splicing variants in the 22rv1 hormone-refractory prostate cancer (pca) cell line. Hum.Mutat. 2010, 31, 74–80. [Google Scholar]
  42. Hu, R.; Dunn, T.A.; Wei, S.; Isharwal, S.; Veltri, R.W.; Humphreys, E.; Han, M.; Partin, A.W.; Vessella, R.L.; Isaacs, W.B.; Bova, G.S.; Luo, J. Ligand-independent androgen receptor variants derived from splicing of cryptic exons signify hormone-refractory prostate cancer. Cancer Res. 2009, 69, 16–22. [Google Scholar]
  43. Dehm, S.M.; Schmidt, L.J.; Heemers, H.V.; Vessella, R.L.; Tindall, D.J. Splicing of a novel androgen receptor exon generates a constitutively active androgen receptor that mediates prostate cancer therapy resistance. Cancer Res. 2008, 68, 5469–5477. [Google Scholar]
  44. Jagla, M.; Feve, M.; Kessler, P.; Lapouge, G.; Erdmann, E.; Serra, S.; Bergerat, J.P.; Ceraline, J. A splicing variant of the androgen receptor detected in a metastatic prostate cancer exhibits exclusively cytoplasmic actions. Endocrinology 2007, 148, 4334–4343. [Google Scholar]
  45. Yeh, S.; Sampson, E.R.; Lee, D.K.; Kim, E.; Hsu, C.L.; Chen, Y.L.; Chang, H.C.; Altuwaijri, S.; Huang, K.E.; Chang, C. Functional analysis of androgen receptor n-terminal and ligand binding domain interacting coregulators in prostate cancer. J. Formos. Med. Assoc. 2000, 99, 885–894. [Google Scholar]
  46. Linja, M.J.; Porkka, K.P.; Kang, Z.; Savinainen, K.J.; Janne, O.A.; Tammela, T.L.; Vessella, R.L.; Palvimo, J.J.; Visakorpi, T. Expression of androgen receptor coregulators in prostate cancer. Clin. Cancer Res. 2004, 10, 1032–1040. [Google Scholar]
  47. Rahman, M.; Miyamoto, H.; Chang, C. Androgen receptor coregulators in prostate cancer: Mechanisms and clinical implications. Clin. Cancer Res. 2004, 10, 2208–2219. [Google Scholar]
  48. Chmelar, R.; Buchanan, G.; Need, E.F.; Tilley, W.; Greenberg, N.M. Androgen receptor coregulators and their involvement in the development and progression of prostate cancer. Int. J. Cancer 2007, 120, 719–733. [Google Scholar]
  49. Nickerson, T.; Chang, F.; Lorimer, D.; Smeekens, S.P.; Sawyers, C.L.; Pollak, M. In vivo progression of lapc-9 and lncap prostate cancer models to androgen independence is associated with increased expression of insulin-like growth factor i (IGF-i) and IGF-i receptor (IGF-ir). Cancer Res. 2001, 61, 6276–6280. [Google Scholar]
  50. Nickerson, T.; Miyake, H.; Gleave, M.E.; Pollak, M. Castration-induced apoptosis of androgen-dependent shionogi carcinoma is associated with increased expression of genes encoding insulinlike growth factor-binding proteins. Cancer Res. 1999, 59, 3392–3395. [Google Scholar]
  51. Gennigens, C.; Menetrier-Caux, C.; Droz, J.P. Insulin-like growth factor (IGF) family and prostate cancer. Crit. Rev. Oncol. Hematol. 2006, 58, 124–145. [Google Scholar]
  52. Rowlands, M.A.; Gunnell, D.; Harris, R.; Vatten, L.J.; Holly, J.M.; Martin, R.M. Circulating insulin-like growth factor peptides and prostate cancer risk: A systematic review and meta-analysis. Int. J. Cancer 2009, 124, 2416–2429. [Google Scholar]
  53. Kumar, R.; Srinivasan, S.; Koduru, S.; Pahari, P.; Rohr, J.; Kyprianou, N.; Damodaran, C. Psoralidin, an herbal molecule, inhibits phosphatidylinositol 3-kinase-mediated akt signaling in androgen-independent prostate cancer cells. Cancer Prev. Res. (Phila) 2009, 2, 234–243. [Google Scholar]
  54. Pfeil, K.; Eder, I.E.; Putz, T.; Ramoner, R.; Culig, Z.; Ueberall, F.; Bartsch, G.; Klocker, H. Long-term androgen-ablation causes increased resistance to PI3K/AKT pathway inhibition in prostate cancer cells. Prostate 2004, 58, 259–268. [Google Scholar]
  55. Bertram, J.; Peacock, J.W.; Fazli, L.; Mui, A.L.; Chung, S.W.; Cox, M.E.; Monia, B.; Gleave, M.E.; Ong, C.J. Loss of pten is associated with progression to androgen independence. Prostate 2006, 66, 895–902. [Google Scholar]
  56. Sircar, K.; Yoshimoto, M.; Monzon, F.A.; Koumakpayi, I.H.; Katz, R.L.; Khanna, A.; Alvarez, K.; Chen, G.; Darnel, A.D.; Aprikian, A.G.; Saad, F.; Bismar, T.A.; Squire, J.A. Pten genomic deletion is associated with p-akt and ar signalling in poorer outcome, hormone refractory prostate cancer. J. Pathol. 2009, 218, 505–513. [Google Scholar]
  57. Huang, H.; Cheville, J.C.; Pan, Y.; Roche, P.C.; Schmidt, L.J.; Tindall, D.J. Pten induces chemosensitivity in pten-mutated prostate cancer cells by suppression of BCL-2 expression. J. Biol. Chem. 2001, 276, 38830–38836. [Google Scholar]
  58. Kojima, S.; Inahara, M.; Suzuki, H.; Ichikawa, T.; Furuya, Y. Implications of insulin-like growth factor-i for prostate cancer therapies. Int. J. Urol. 2009, 16, 161–167. [Google Scholar]
  59. Roberts, C.T., Jr. Igf-1 and prostate cancer. Novartis Found Symp. 2004, 262, 193–199, discussion 199-204, 265-198. [Google Scholar]
  60. Wu, J.D.; Haugk, K.; Woodke, L.; Nelson, P.; Coleman, I.; Plymate, S.R. Interaction of IGF signaling and the androgen receptor in prostate cancer progression. J. Cell Biochem. 2006, 99, 392–401. [Google Scholar]
  61. Craft, N.; Shostak, Y.; Carey, M.; Sawyers, C.L. A mechanism for hormone-independent prostate cancer through modulation of androgen receptor signaling by the Her-2/Neu tyrosine kinase. Nat. Med. 1999, 5, 280–285. [Google Scholar]
  62. Reese, D.M.; Small, E.J.; Magrane, G.; Waldman, F.M.; Chew, K.; Sudilovsky, D. Her2 protein expression and gene amplification in androgen-independent prostate cancer. Am. J. Clin. Pathol. 2001, 116, 234–239. [Google Scholar]
  63. Okegawa, T.; Kinjo, M.; Nutahara, K.; Higashihara, E. Pretreatment serum level of Her2/Nue as a prognostic factor in metastatic prostate cancer patients about to undergo endocrine therapy. Int. J. Urol. 2006, 13, 1197–1201. [Google Scholar]
  64. Signoretti, S.; Montironi, R.; Manola, J.; Altimari, A.; Tam, C.; Bubley, G.; Balk, S.; Thomas, G.; Kaplan, I.; Hlatky, L.; Hahnfeldt, P.; Kantoff, P.; Loda, M. Her-2-Neu expression and progression toward androgen independence in human prostate cancer. J. Natl. Cancer Inst. 2000, 92, 1918–1925. [Google Scholar]
  65. Calvo, B.F.; Levine, A.M.; Marcos, M.; Collins, Q.F.; Iacocca, M.V.; Caskey, L.S.; Gregory, C.W.; Lin, Y.; Whang, Y.E.; Earp, H.S.; Mohler, J.L. Human epidermal receptor-2 expression in prostate cancer. Clin. Cancer Res. 2003, 9, 1087–1097. [Google Scholar]
  66. Cho, K.S.; Lee, J.S.; Cho, N.H.; Park, K.; Ham, W.S.; Choi, Y.D. Gene amplification and mutation analysis of epidermal growth factor receptor in hormone refractory prostate cancer. Prostate 2008, 68, 803–808. [Google Scholar]
  67. Carles, J.; Lloreta, J.; Salido, M.; Font, A.; Suarez, M.; Baena, V.; Nogue, M.; Domenech, M.; Fabregat, X. Her-2/neu expression in prostate cancer: A dynamic process? Clin Cancer Res. 2004, 10, 4742–4745. [Google Scholar]
  68. Bartlett, J.M.; Brawley, D.; Grigor, K.; Munro, A.F.; Dunne, B.; Edwards, J. Type i receptor tyrosine kinases are associated with hormone escape in prostate cancer. J. Pathol. 2005, 205, 522–529. [Google Scholar]
  69. Shi, Y.; Brands, F.H.; Chatterjee, S.; Feng, A.C.; Groshen, S.; Schewe, J.; Lieskovsky, G.; Cote, R.J. Her-2/neu expression in prostate cancer: High level of expression associated with exposure to hormone therapy and androgen independent disease. J. Urol. 2001, 166, 1514–1519. [Google Scholar]
  70. Edwards, J.; Traynor, P.; Munro, A.F.; Pirret, C.F.; Dunne, B.; Bartlett, J.M. The role of Her1-Her4 and EGFRVIII in hormone-refractory prostate cancer. Clin. Cancer Res. 2006, 12, 123–130. [Google Scholar]
  71. Di Lorenzo, G.; Autorino, R.; De Laurentiis, M.; Cindolo, L.; D'Armiento, M.; Bianco, A.R.; De Placido, S. Her-2/Neu receptor in prostate cancer development and progression to androgen independence. Tumori 2004, 90, 163–170. [Google Scholar]
  72. Wen, Y.; Hu, M.C.-T.; Makino, K.; Spohn, B.; Bartholomeusz, G.; Yan, D.-H.; Hung, M.-C. Her-2/Neu promotes androgen-independent survival and growth of prostate cancer cells through the AKT pathway. Cancer Res. 2000, 60, 6841–6845. [Google Scholar]
  73. Mellinghoff, I.K.; Vivanco, I.; Kwon, A.; Tran, C.; Wongvipat, J.; Sawyers, C.L. Her2/Neu kinase-dependent modulation of androgen receptor function through effects on DNA binding and stability. Cancer Cell 2004, 6, 517–527. [Google Scholar]
  74. Khandrika, L.; Lieberman, R.; Koul, S.; Kumar, B.; Maroni, P.; Chandhoke, R.; Meacham, R.B.; Koul, H.K. Hypoxia-associated p38 mitogen-activated protein kinase-mediated androgen receptor activation and increased HIF-1 alpha levels contribute to emergence of an aggressive phenotype in prostate cancer. Oncogene 2009, 28, 1248–1260. [Google Scholar]
  75. Anton Aparicio, L.M.; Cassinello Espinosa, J.; Garcia Campelo, R.; Gomez Veiga, F.; Diaz Prado, S.; Aparicio Gallego, G. Prostate carcinoma and stem cells. Clin. Transl. Oncol. 2007, 9, 66–76. [Google Scholar]
  76. Chesire, D.R.; Isaacs, W.B. Ligand-dependent inhibition of beta-catenin/TCF signaling by androgen receptor. Oncogene 2002, 21, 8453–8469. [Google Scholar]
  77. Yang, F.; Li, X.; Sharma, M.; Sasaki, C.Y.; Longo, D.L.; Lim, B.; Sun, Z. Linking beta-catenin to androgen-signaling pathway. J. Biol. Chem. 2002, 277, 11336–11344. [Google Scholar]
  78. Truica, C.I.; Byers, S.; Gelmann, E.P. Beta-catenin affects androgen receptor transcriptional activity and ligand specificity. Cancer Res. 2000, 60, 4709–4713. [Google Scholar]
  79. Chesire, D.R.; Isaacs, W.B. Beta-catenin signaling in prostate cancer: An early perspective. Endocr. Relat. Cancer 2003, 10, 537–560. [Google Scholar]
  80. Lu, W.; Tinsley, H.N.; Keeton, A.; Qu, Z.; Piazza, G.A.; Li, Y. Suppression of wnt/beta-catenin signaling inhibits prostate cancer cell proliferation. Eur. J. Pharmacol. 2009, 602, 8–14. [Google Scholar]
  81. Chen, G.; Shukeir, N.; Potti, A.; Sircar, K.; Aprikian, A.; Goltzman, D.; Rabbani, S.A. Up-regulation of Wnt-1 and beta-catenin production in patients with advanced metastatic prostate carcinoma: Potential pathogenetic and prognostic implications. Cancer 2004, 101, 1345–1356. [Google Scholar]
  82. de la Taille, A.; Rubin, M.A.; Chen, M.W.; Vacherot, F.; de Medina, S.G.; Burchardt, M.; Buttyan, R.; Chopin, D. Beta-catenin-related anomalies in apoptosis-resistant and hormone-refractory prostate cancer cells. Clin. Cancer Res. 2003, 9, 1801–1807. [Google Scholar]
  83. Wang, G.; Wang, J.; Sadar, M.D. Crosstalk between the androgen receptor and beta-catenin in castrate-resistant prostate cancer. Cancer Res. 2008, 68, 9918–9927. [Google Scholar]
  84. Verras, M.; Brown, J.; Li, X.; Nusse, R.; Sun, Z. Wnt3a growth factor induces androgen receptor-mediated transcription and enhances cell growth in human prostate cancer cells. Cancer Res. 2004, 64, 8860–8866. [Google Scholar]
  85. Schweizer, L.; Rizzo, C.A.; Spires, T.E.; Platero, J.S.; Wu, Q.; Lin, T.A.; Gottardis, M.M.; Attar, R.M. The androgen receptor can signal through Wnt/beta-catenin in prostate cancer cells as an adaptation mechanism to castration levels of androgens. BMC Cell Biol. 2008, 9, 4. [Google Scholar]
  86. Cai, C.; Wang, H.; Xu, Y.; Chen, S.; Balk, S.P. Reactivation of androgen receptor-regulated tmprss2:Erg gene expression in castration-resistant prostate cancer. Cancer Res. 2009, 69, 6027–6032. [Google Scholar]
  87. Locke, J.A.; Guns, E.S.; Lubik, A.A.; Adomat, H.H.; Hendy, S.C.; Wood, C.A.; Ettinger, S.L.; Gleave, M.E.; Nelson, C.C. Androgen levels increase by intratumoral de novo steroidogenesis during progression of castration-resistant prostate cancer. Cancer Res. 2008, 68, 6407–6415. [Google Scholar]
  88. Yuan, X.; Balk, S.P. Mechanisms mediating androgen receptor reactivation after castration. Urol. Oncol. 2009, 27, 36–41. [Google Scholar]
  89. Mostaghel, E.A.; Page, S.T.; Lin, D.W.; Fazli, L.; Coleman, I.M.; True, L.D.; Knudsen, B.; Hess, D.L.; Nelson, C.C.; Matsumoto, A.M.; Bremner, W.J.; Gleave, M.E.; Nelson, P.S. Intraprostatic androgens and androgen-regulated gene expression persist after testosterone suppression: Therapeutic implications for castration-resistant prostate cancer. Cancer Res. 2007, 67, 5033–5041. [Google Scholar]
  90. Lawson, D.A.; Witte, O.N. Stem cells in prostate cancer initiation and progression. J. Clin. Invest. 2007, 117, 2044–2050. [Google Scholar]
  91. Lang, S.H.; Frame, F.M.; Collins, A.T. Prostate cancer stem cells. J. Pathol. 2009, 217, 299–306. [Google Scholar]
  92. Maitland, N.J.; Collins, A.T. Prostate cancer stem cells: A new target for therapy. J. Clin. Oncol. 2008, 26, 2862–2870. [Google Scholar]
Back to TopTop