Implications of Bcl-2 and its interplay with other molecules and signaling pathways in prostate cancer progression

Expert Opinion on Therapeutic Targets

Volumn 21, Issue 9, 2017, Pages 911-920

  Kim, Ju Ha ^a   Lee, Hyemin ^a   Shin, Eun Ah ^a   Kim, Dong Hee ^a   Choi, Jhin Baek ^a   Kim, Sung Hoon ^a  

^a Kyung Hee University   (South Korea)

Author keywords

AKT; androgen; BCL 2; microRNAs; prostate cancer; PTEN

Indexed keywords

ANDROGEN; BECLIN 1; FK 506 BINDING PROTEIN; FK 506 BINDING PROTEIN 38; GALECTIN 3; IMMUNOGLOBULIN ENHANCER BINDING PROTEIN; MICRORNA; MITOGEN ACTIVATED PROTEIN KINASE; NUCLEAR RECEPTOR NUR77; PHOSPHATIDYLINOSITOL 3,4,5 TRISPHOSPHATE 3 PHOSPHATASE; PROTEIN BCL 2; PROTEIN BCL 2 INHIBITOR; PROTEIN INHIBITOR; PROTEIN KINASE B; PROTEIN P53; STAT3 PROTEIN; UNCLASSIFIED DRUG;

AUTOPHAGY; CANCER GROWTH; CARCINOGENESIS; CLINICAL TRIAL (TOPIC); HUMAN; NONHUMAN; PROSTATE CANCER; PROTEIN DEPLETION; PROTEIN FUNCTION; REVIEW; SIGNAL TRANSDUCTION; UPREGULATION; ANIMAL; DISEASE COURSE; GENE EXPRESSION REGULATION; GENETICS; MALE; METABOLISM; PATHOLOGY; PROSTATE TUMOR;

ANDROGENS; ANIMALS; DISEASE PROGRESSION; GENE EXPRESSION REGULATION, NEOPLASTIC; HUMANS; MALE; PROSTATIC NEOPLASMS; PROTO-ONCOGENE PROTEINS C-BCL-2; SIGNAL TRANSDUCTION; UP-REGULATION;

EID: 85028688807     PISSN: 14728222     EISSN: 17447631     Source Type: Journal    
DOI: 10.1080/14728222.2017.1369044     Document Type: Review

References (141)

1. Torre LA, Siegel RL, Ward EM, et al. Global cancer incidence and mortality rates and trends–an update. Cancer Epidemiol Biomarkers Prev. 2016;25(1):16–27.
2. Siegel RL, Miller KD, Jemal A., Cancer statistics, 2016. CA Cancer J Clin. 2016;66:7–30.
3. Feldman BJ, Feldman D., The development of androgen-independent prostate cancer. Nat Rev Cancer. 2001;1:34–45.•• Excellent overview of five signaling pathways for the development of AIPC.
4. Maughan BL, Antonarakis ES. Androgen pathway resistance in prostate cancer and therapeutic implications. Expert Opin Pharmacother. 2015;16:1521–1537.• Overall analysis of androgen therapy resistance mechanisms and the optimal treatment for CRPC.
5. Assikis VJ, Simons JW. Novel therapeutic strategies for androgen-independent prostate cancer:an update. Semin Oncol. 2004;31:26–32.
6. Hockenbery D, Nunez G, Milliman C, et al. Bcl-2 is an inner mitochondrial membrane protein that blocks programmed cell death. Nature. 1990;348:334–336.
7. Tsujimoto Y, Finger LR, Yunis J, et al. Cloning of the chromosome breakpoint of neoplastic B cells with the t(14;18) chromosome translocation. Science. 1984;226:1097–1099.
8. Ohigashi T, Ueno M, Nonaka S, et al. Bcl-2 and androgen receptor gene expression in androgen-independent subclone derived from mouse androgen-dependent cells. Cancer Invest. 2002;20:730–736.
9. McDonnell TJ, Navone NM, Troncoso P, et al. Expression of bcl-2 oncoprotein and p53 protein accumulation in bone marrow metastases of androgen independent prostate cancer. J Urol. 1997;157:569–574.
10. Furuya Y, Krajewski S, Epstein JI, et al. Expression of bcl-2 and the progression of human and rodent prostatic cancers. Clin Cancer Res. 1996;2:389–398.
11. Gleave ME, Miayake H, Goldie J, et al. Targeting bcl-2 gene to delay androgen-independent progression and enhance chemosensitivity in prostate cancer using antisense bcl-2 oligodeoxynucleotides. Urology. 1999;54:36–46.
12. Lin Y, Fukuchi J, Hiipakka RA, et al. Up-regulation of Bcl-2 is required for the progression of prostate cancer cells from an androgen-dependent to an androgen-independent growth stage. Cell Res. 2007;17:531–536.
13. Miayake H, Tolcher A, Gleave ME. Chemosensitization and delayed androgen-independent recurrence of prostate cancer with the use of antisense Bcl-2 oligodeoxynucleotides. J Natl Cancer Inst. 2000;92:34–41.
14. Karnak D, Xu L. Chemosensitization of prostate cancer by modulating Bcl-2 family proteins. Curr Drug Targets. 2010;11(6):699–707.
15. Leung S, Miyake H, Zellweger T, et al. Synergistic chemosensitization and inhibition of progression to androgen independence by antisense Bcl-2 oligodeoxynucleotide and paclitaxel in the LNCaP prostate tumor model. Int J Cancer. 2001;91:846–850.
16. Sarkar S, Pradhan A, Das SK, et al. Novel therapy of prostate cancer employing a combination of viral-based immunotherapy and a small molecule BH3 mimetic. Oncoimmunology. 2016;5:e1078059.
17. Aragon-Ching JB, Dahut WL. Chemotherapy in androgen-independent prostate cancer (AIPC):what’s next after taxane progression? Cancer Ther. 2007;5A:151–160.
18. Kang MH, Reynolds CP. Bcl-2 inhibitors:targeting mitochondrial apoptotic pathways in cancer therapy. Clin Cancer Res. 2009;15:1126–1132.
19. R D. Navitoclax and abiraterone acetate with or without hydroxychloroquine in treating patients with progressive metastatic castrate refractory prostate cancer. Clinicaltrialsgov:NCT01828476. 2013
20. Sonpavde G, Matveev V, Burke JM, et al. Randomized phase II trial of docetaxel plus prednisone in combination with placebo or AT-101, an oral small molecule Bcl-2 family antagonist, as first-line therapy for metastatic castration-resistant prostate cancer. Ann Oncol. 2011;23:1803–1808.
21. Yoshino T, Shiina H, Urakami S, et al. Bcl-2 expression as a predictive marker of hormone-refractory prostate cancer treated with taxane-based chemotherapy. Clin Cancer Res. 2006;12:6116–6124.
22. Vaux DL, Cory S, Adams JM. Bcl-2 gene promotes haemopoietic cell survival and cooperates with c-myc to immortalize pre-B cells. Nature. 1988;335:440–442.
23. Lithgow T, Van Driel R, Bertram JF, et al. The protein product of the oncogene bcl-2 is a component of the nuclear envelope, the endoplasmic reticulum, and the outer mitochondrial membrane. Cell Growth Differ. 1994;5:411–417.
24. Verma YK, Gangenahalli GU, Singh VK, et al. Cell death regulation by B-cell lymphoma protein. Apoptosis. 2006;11:459–471.
25. Kurinna S, Konopleva M, Palla SL, et al. Bcl2 phosphorylation and active PKC alpha are associated with poor survival in AML. Leukemia. 2006;20:1316–1319.
26. Perez-Galan P, Roue G, Lopez-Guerra M, et al. BCL-2 phosphorylation modulates sensitivity to the BH3 mimetic GX15-070 (Obatoclax) and reduces its synergistic interaction with bortezomib in chronic lymphocytic leukemia cells. Leukemia. 2008;22:1712–1720.
27. Haldar S, Jena N, Croce CM. Inactivation of Bcl-2 by phosphorylation. Proc Natl Acad Sci U S A. 1995;92:4507–4511.
28. Czabotar PE, Lessene G, Strasser A, et al. Control of apoptosis by the BCL-2 protein family:implications for physiology and therapy. Nat Rev Mol Cell Biol. 2014;15:49–63.• Excellent overview on functions and structures of BCL-2 protein family.
29. Kahn B, Collazo J, Kyprianou N. Androgen receptor as a driver of therapeutic resistance in advanced prostate cancer. Int J Biol Sci. 2014;10:588–595.
30. Green SM, Mostaghel EA, Nelson PS. Androgen action and metabolism in prostate cancer. Mol Cell Endocrinol. 2012;360:3–13.
31. Bonkhoff H, Fixemer T, Remberger K. Relation between Bcl-2, cell proliferation, and the androgen receptor status in prostate tissue and precursors of prostate cancer. Prostate. 1998;34:251–258.
32. Schweizer MT, Plymate SR. Targeting constitutively active androgen receptor splice variants in castration resistant prostate cancer. Expert Opin Ther Targets. 2016;20:903–906.
33. Raffo AJ, Perlman H, Chen MW, et al. Overexpression of bcl-2 protects prostate cancer cells from apoptosis in vitro and confers resistance to androgen depletion in vivo. Cancer Res. 1995;55:4438–4445.
34. Xu J, Qiu Y. Role of androgen receptor splice variants in prostate cancer metastasis. Asian J Urol. 2016;3:177–184.
35. Harris WP, Mostaghel EA, Nelson PS, et al. Androgen deprivation therapy:progress in understanding mechanisms of resistance and optimizing androgen depletion. Nat Clinical Practice Urol. 2009;6:76–85.
36. Hughes IA, Werner R, Bunch T, et al. Androgen insensitivity syndrome. Semin Reprod Med. 2012;30:432–442.
37. Culig Z, Hoffmann J, Erdel M, et al. Switch from antagonist to agonist of the androgen receptor bicalutamide is associated with prostate tumour progression in a new model system. Br J Cancer. 1999;81:242–251.
38. Hobisch A, Hoffmann J, Lambrinidis L, et al. Antagonist/agonist balance of the nonsteroidal antiandrogen bicalutamide (Casodex) in a new prostate cancer model. Urol Int. 2000;65:73–79.
39. Huang H, Zegarra-Moro OL, Benson D, et al. Androgens repress Bcl-2 expression via activation of the retinoblastoma (RB) protein in prostate cancer cells. Oncogene. 2004;23:2161–2176.• Definitive demonstration that AR blocks BCL-2 via RB activation in prostate cancer.
40. Parrondo R, de Las Pozas A, Reiner T, et al. ABT-737, a small molecule Bcl-2/Bcl-xL antagonist, increases antimitotic-mediated apoptosis in human prostate cancer cells. PeerJ. 2013;1:e144.
41. Nemes A, Tomuleasa C, Kacso G. The androgen receptor remains a key player in metastatic hormone-refractory prostate cancer. Implications for new treatments. J Buon. 2014;19:357–364.
42. Ishikura N, Kawata H, Nishimoto A, et al. Establishment and characterization of an androgen receptor-dependent, androgen-independent human prostate cancer cell line, LNCaP-CS10. Prostate. 2010;70:457–466.
43. Deng Q, Tang DG. Androgen receptor and prostate cancer stem cells:biological mechanisms and clinical implications. Endocr Relat Cancer. 2015;22:T209–T220.
44. Marques RB, Dits NF, Erkens-Schulze S, et al. Bypass mechanisms of the androgen receptor pathway in therapy-resistant prostate cancer cell models. PloS One. 2010;5:e13500.
45. Klaassen Z, Howard LE, de Hoedt A, et al. Factors predicting skeletal-related events in patients with bone metastatic castration-resistant prostate cancer. Cancer. 2017;123:1528–1535.
46. So A, Chin J, Fleshner N, et al. Management of skeletal-related events in patients with advanced prostate cancer and bone metastases:incorporating new agents into clinical practice. Can Urol Assoc J. 2012;6:465–470.
47. El-Amm J, Aragon-Ching JB. Targeting bone metastases in metastatic castration-resistant prostate cancer. Clin Med Insights Oncol. 2016;10(Suppl 1):11–19.
48. Qian G, Hao S, Yang D, et al. P15, MDM2, NF-kappaB, and Bcl-2 expression in primary bone tumor and correlation with tumor formation and metastasis. Int J Clin Exp Pathol. 2015;8:14885–14892.
49. Gomez-Veiga F, Ponce-Reixa J, Martinez-Breijo S, et al. Advances in prevention and treatment of bone metastases in prostate cancer. Role of RANK/RANKL inhibition. Actas Urol Esp. 2013;37:292–304.
50. Hammerich KH, Donahue TF, Rosner IL, et al. Alkaline phosphatase velocity predicts overall survival and bone metastasis in patients with castration-resistant prostate cancer. Urol Oncol. 2017;35:460.e21-460.e28.
51. Migliaccio A, Castoria G, Di Domenico M, et al. Steroid-induced androgen receptor-oestradiol receptor beta-Src complex triggers prostate cancer cell proliferation. Embo J. 2000;19:5406–5417.
52. Lee LF, Louie MC, Desai SJ, et al. Interleukin-8 confers androgen-independent growth and migration of LNCaP:differential effects of tyrosine kinases Src and FAK. Oncogene. 2004;23:2197–2205.
53. Nakazawa M, Paller C, Kyprianou N. Mechanisms of therapeutic resistance in prostate cancer. Curr Oncol Rep. 2017;19:13.
54. Saad F. Src as a therapeutic target in men with prostate cancer and bone metastases. BJU Int. 2009;103:434–440.
55. Dong JT, Sipe TW, Hyytinen ER, et al. PTEN/MMAC1 is infrequently mutated in pT2 and pT3 carcinomas of the prostate. Oncogene. 1998;17:1979–1982.
56. Carnero A, Blanco-Aparicio C, Renner O, et al. The PTEN/PI3K/AKT signalling pathway in cancer, therapeutic implications. Curr Cancer Drug Targets. 2008;8:187–198.
57. Conley-LaComb MK, Saliganan A, Kandagatla P, et al. PTEN loss mediated Akt activation promotes prostate tumor growth and metastasis via CXCL12/CXCR4 signaling. Mol Cancer. 2013;12:85.
58. Nan B, Snabboon T, Unni E, et al. The PTEN tumor suppressor is a negative modulator of androgen receptor transcriptional activity. J Mol Endocrinol. 2003;31:169–183.
59. Catz SD, Johnson JL. BCL-2 in prostate cancer:a minireview. Apoptosis. 2003;8:29–37.
60. Peacock JW, Palmer J, Fink D, et al. PTEN loss promotes mitochondrially dependent type II Fas-induced apoptosis via PEA-15. Mol Cell Biol. 2009;29:1222–1234.
61. Huang H, Cheville JC, Pan Y, et al. PTEN induces chemosensitivity in PTEN-mutated prostate cancer cells by suppression of Bcl-2 expression. J Biol Chem. 2001;276:38830–38836.
62. Calastretti A, Gatti G, Quaresmini C, et al. Down-modulation of Bcl-2 sensitizes PTEN-mutated prostate cancer cells to starvation and taxanes. Prostate. 2014;74:1411–1422.
63. Rosser CJ, Tanaka M, Pisters LL, et al. Adenoviral-mediated PTEN transgene expression sensitizes Bcl-2-expressing prostate cancer cells to radiation. Cancer Gene Ther. 2004;11:273–279.
64. Deng X, Gao F, Flagg T, et al. Bcl2’s flexible loop domain regulates p53 binding and survival. Mol Cell Biol. 2006;26:4421–4434.
65. Ringer L, Sirajuddin P, Tricoli L, et al. The induction of the p53 tumor suppressor protein bridges the apoptotic and autophagic signaling pathways to regulate cell death in prostate cancer cells. Oncotarget. 2014;5:10678–10691.
66. Huang K, Tang Y, He L, et al. MicroRNA-340 inhibits prostate cancer cell proliferation and metastasis by targeting the MDM2-p53 pathway. Oncol Rep. 2016;35:887–895.
67. Silvestrini R, Veneroni S, Daidone MG, et al. The Bcl-2 protein:a prognostic indicator strongly related to p53 protein in lymph node-negative breast cancer patients. J Natl Cancer Inst. 1994;86:499–504.
68. Wen Z, Zhong Z, Darnell JE, Jr. Maximal activation of transcription by Stat1 and Stat3 requires both tyrosine and serine phosphorylation. Cell. 1995;82:241–250.
69. Chen Y, Li T, Yu X, et al. The RTK/ERK pathway is associated with prostate cancer risk on the SNP level:a pooled analysis of 41 sets of data from case-control studies. Gene. 2014;534:286–297.
70. Rubenstein M, Hollowell CM, Guinan P. Additional compensatory mechanisms altering antisense oligonucleotide suppression of BCL2:effects upon AKT1 and STAT3. In Vivo. 2014;28:867–870.• Demonstration that BCL-2-specific-target effects upon AKT1 and STAT3 signaling.
71. Rubenstein M, Hollowell CM, Guinan P. Suppression of BCL2 by antisense oligonucleotides and compensation by non-targeted genes may enhance tumor proliferation. In Vivo. 2015;29:687–693. [Research Support, Non-U.S. Gov’t].
72. Rubenstein M, Hollowell CM, Guinan P. In LNCaP cells enhanced expression of both androgen receptor and costimulatory protein p300 compensate for antisense oligonucleotide suppression of bcl-2. Ther Adv Urol. 2011;3:243–250.
73. Zhang D, He D, Xue Y, et al. PrLZ protects prostate cancer cells from apoptosis induced by androgen deprivation via the activation of Stat3/Bcl-2 pathway. Cancer Res. 2011;71:2193–2202.
74. You L, Wang Z, Li H, et al. The role of STAT3 in autophagy. Autophagy. 2015;11:729–739.
75. Real PJ, Sierra A, De Juan A, et al. Resistance to chemotherapy via Stat3-dependent overexpression of Bcl-2 in metastatic breast cancer cells. Oncogene. 2002;21:7611–7618.
76. Nielsen M, Kaestel CG, Eriksen KW, et al. Inhibition of constitutively activated Stat3 correlates with altered Bcl-2/Bax expression and induction of apoptosis in mycosis fungoides tumor cells. Leukemia. 1999;13:735–738.
77. Al Zaid Siddiquee K, Turkson J. STAT3 as a target for inducing apoptosis in solid and hematological tumors. Cell Res. 2008;18:254–267.
78. Ghosh S, Dass JF. Study of pathway cross-talk interactions with NF-kappaB leading to its activation via ubiquitination or phosphorylation:a brief review. Gene. 2016;584:97–109.
79. Malinowska K, Neuwirt H, Cavarretta IT, et al. Interleukin-6 stimulation of growth of prostate cancer in vitro and in vivo through activation of the androgen receptor. Endocr Relat Cancer. 2009;16:155–169.
80. Catz SD, Johnson JL. Transcriptional regulation of bcl-2 by nuclear factor kappa B and its significance in prostate cancer. Oncogene. 2001;20:7342–7351.
81. Wang HG, Rapp UR, Reed JC. Bcl-2 targets the protein kinase Raf-1 to mitochondria. Cell. 1996;87:629–638.
82. Ravi RK, McMahon M, Yangang Z, et al. Raf-1-induced cell cycle arrest in LNCaP human prostate cancer cells. J Cell Biochem. 1999;72:458–469.
83. De Chiara G, Marcocci ME, Torcia M, et al. Bcl-2 Phosphorylation by p38 MAPK:identification of target sites and biologic consequences. J Biol Chem. 2006;281:21353–21361.
84. Chaudhary P, Vishwanatha JK. c-Jun NH2-terminal kinase-induced proteasomal degradation of c-FLIPL/S and Bcl2 sensitize prostate cancer cells to Fas- and mitochondria-mediated apoptosis by tetrandrine. Biochem Pharmacol. 2014;91:457–473.
85. Zelivianski S, Spellman M, Kellerman M, et al. ERK inhibitor PD98059 enhances docetaxel-induced apoptosis of androgen-independent human prostate cancer cells. Int J Cancer. 2003;107:478–485.
86. Shin JA, Kim LH, Lee SJ, et al. Targeting ERK1/2-bim signaling cascades by BH3-mimetic ABT-737 as an alternative therapeutic strategy for oral cancer. Oncotarget. 2015;6:35667–35683.
87. Guo JY, White E. Autophagy, Metabolism, and Cancer. Cold Spring Harb Symp Quant Biol. 2017;81:73–78.
88. Liang XH, Kleeman LK, Jiang HH, et al. Protection against fatal Sindbis virus encephalitis by beclin, a novel Bcl-2-interacting protein. J Virol. 1998;72:8586–8596.
89. Marquez RT, Xu L. Bcl-2:beclin 1 complex:multiple, mechanisms regulating autophagy/apoptosis toggle switch. Am J Cancer Res. 2012;2:214–221.
90. Oberstein A, Jeffrey PD, Shi Y. Crystal structure of the Bcl-XL-Beclin 1 peptide complex:beclin 1 is a novel BH3-only protein. J Biol Chem. 2007;282:13123–13132.
91. Ciechomska IA, Goemans GC, Skepper JN, et al. Bcl-2 complexed with Beclin-1 maintains full anti-apoptotic function. Oncogene. 2009;28:2128–2141.
92. Lian J, Karnak D, Xu L. The Bcl-2-Beclin 1 interaction in (-)-gossypol-induced autophagy versus apoptosis in prostate cancer cells. Autophagy. 2010;6:1201–1203.
93. Lian J, Wu X, He F, et al. A natural BH3 mimetic induces autophagy in apoptosis-resistant prostate cancer via modulating Bcl-2-Beclin1 interaction at endoplasmic reticulum. Cell Death Differ. 2011;18:60–71.• Significant evidence that natural BCL-2 mimetics, gossypol, induces autophagy by blocking BCL-2-Beclin-1 interaction.
94. Rah B, Ur Rasool R, Nayak D, et al. PAWR-mediated suppression of BCL2 promotes switching of 3-azido withaferin A (3-AWA)-induced autophagy to apoptosis in prostate cancer cells. Autophagy. 2015;11:314–331.
95. Di Rita A, Strappazzon F. AMBRA1, a novel BH3-like protein:new insights into the AMBRA1-BCL2-family proteins relationship. Int Rev Cell Mol Biol. 2017;330:85–113.
96. Strappazzon F, Di Rita A, Cianfanelli V, et al. Prosurvival AMBRA1 turns into a proapoptotic BH3-like protein during mitochondrial apoptosis. Autophagy. 2016;12:963–975.
97. Falasca L, Torino F, Marconi M, et al. AMBRA1 and SQSTM1 expression pattern in prostate cancer. Apoptosis. 2015;20:1577–1586.
98. Cho WC. MicroRNAs in cancer - from research to therapy. Biochim Biophys Acta. 2010;1805:209–217.
99. Altarejos JY, Montminy M. CREB and the CRTC co-activators:sensors for hormonal and metabolic signals. Nat Rev Mol Cell Biol. 2011;12:141–151.
100. Ji Q, Hao X, Zhang M, et al. MicroRNA miR-34 inhibits human pancreatic cancer tumor-initiating cells. PLoS One. 2009;4:e6816.
101. Cheng CY, Hwang CI, Corney DC, et al. miR-34 cooperates with p53 in suppression of prostate cancer by joint regulation of stem cell compartment. Cell Rep. 2014;6:1000–1007.
102. Liu C, Kelnar K, Liu B, et al. The microRNA miR-34a inhibits prostate cancer stem cells and metastasis by directly repressing CD44. Nat Med. 2011;17:211–215.
103. Lin PC, Chiu YL, Banerjee S, et al. Epigenetic repression of miR-31 disrupts androgen receptor homeostasis and contributes to prostate cancer progression. Cancer Res. 2013;73:1232–1244.
104. Lynch SM, McKenna MM, Walsh CP, et al. miR-24 regulates CDKN1B/p27 expression in prostate cancer. Prostate. 2016;76:637–648.
105. Cai C, Chen QB, Han ZD, et al. miR-195 inhibits tumor progression by targeting RPS6KB1 in human prostate cancer. Clin Cancer Res. 2015;21:4922–4934.
106. Shi XB, Ma AH, Xue L, et al. miR-124 and androgen receptor signaling inhibitors repress prostate cancer growth by downregulating androgen receptor splice variants, EZH2, and src. Cancer Res. 2015;75:5309–5317.
107. Sacconi A, Biagioni F, Canu V, et al. miR-204 targets Bcl-2 expression and enhances responsiveness of gastric cancer. Cell Death Dis. 2012;3:e423.
108. Pennati M, Lopergolo A, Profumo V, et al. miR-205 impairs the autophagic flux and enhances cisplatin cytotoxicity in castration-resistant prostate cancer cells. Biochem Pharmacol. 2014;87:579–597.
109. Hezova R, Kovarikova A, Srovnal J, et al. MiR-205 functions as a tumor suppressor in adenocarcinoma and an oncogene in squamous cell carcinoma of esophagus. Tumour Biol. 2016;37:8007–8018.
110. Li J, Hu K, Gong G, et al. Upregulation of MiR-205 transcriptionally suppresses SMAD4 and PTEN and contributes to human ovarian cancer progression. Sci Rep. 2017;7:41330.
111. Verdoodt B, Neid M, Vogt M, et al. MicroRNA-205, a novel regulator of the anti-apoptotic protein Bcl2, is downregulated in prostate cancer. Int J Oncol. 2013;43:307–314.
112. Bhatnagar N, Li X, Padi SK, et al. Downregulation of miR-205 and miR-31 confers resistance to chemotherapy-induced apoptosis in prostate cancer cells. Cell Death Dis. 2010;1:e105.
113. Luo G, Wang M, Wu X, et al. Long non-coding RNA MEG3 inhibits cell proliferation and induces apoptosis in prostate cancer. Cell Physiol Biochem. 2015;37:2209–2220.
114. Choi BH, Feng L, Yoon HS. FKBP38 protects Bcl-2 from caspase-dependent degradation. J Biol Chem. 2010;285:9770–9779.
115. Kang CB, Feng L, Chia J, et al. Molecular characterization of FK-506 binding protein 38 and its potential regulatory role on the anti-apoptotic protein Bcl-2. Biochem Biophys Res Commun. 2005;337:30–38.
116. Wang HQ, Nakaya Y, Du Z, et al. Interaction of presenilins with FKBP38 promotes apoptosis by reducing mitochondrial Bcl-2. Hum Mol Genet. 2005;14:1889–1902.
117. Shirane M, Nakayama KI. Inherent calcineurin inhibitor FKBP38 targets Bcl-2 to mitochondria and inhibits apoptosis. Nat Cell Biol. 2003;5:28–37.
118. Lin B, Kolluri SK, Lin F, et al. Conversion of Bcl-2 from protector to killer by interaction with nuclear orphan receptor Nur77/TR3. Cell. 2004;116:527–540.
119. Zhang XK. Targeting Nur77 translocation. Expert Opin Ther Targets. 2007;11:69–79.
120. Yu L, Su YS, Zhao J, et al. Repression of NR4A1 by a chromatin modifier promotes docetaxel resistance in PC-3 human prostate cancer cells. FEBS Lett. 2013;587:2542–2551.
121. Leffler H, Carlsson S, Hedlund M, et al. Introduction to galectins. Glycoconj J. 2004;19:433–440.
122. Akahani S, Nangia-Makker P, Inohara H, et al. Galectin-3:a novel antiapoptotic molecule with a functional BH1 (NWGR) domain of Bcl-2 family. Cancer Res. 1997;57:5272–5276.
123. Yang H, Lei C, Cheng C, et al. The antiapoptotic effect of galectin-3 in human endometrial cells under the regulation of estrogen and progesterone. Biol Reprod. 2012;87:39.
124. Harazono Y, Nakajima K, Raz A. Why anti-Bcl-2 clinical trials fail:a solution. Cancer Metastasis Rev. 2014;33:285–294.
125. Gleave M, Tolcher A, Miyake H, et al. Progression to androgen independence is delayed by adjuvant treatment with antisense Bcl-2 oligodeoxynucleotides after castration in the LNCaP prostate tumor model. Clin Cancer Res. 1999;5:2891–2898.
126. Figg WD. The 2005 leon I. Goldberg young investigator award lecture:development of thalidomide as an angiogenesis inhibitor for the treatment of androgen-independent prostate cancer. Clin Pharmacol Ther. 2006;79:1–8.
127. Paik PK, Rudin CM, Pietanza MC, et al. A phase II study of obatoclax mesylate, a Bcl-2 antagonist, plus topotecan in relapsed small cell lung cancer. Lung Cancer. 2011;74:481–485.
128. Xu H, Krystal GW. Actinomycin D decreases Mcl-1 expression and acts synergistically with ABT-737 against small cell lung cancer cell lines. Clin Cancer Res. 2010;16:4392–4400.
129. Rudin CM, Hann CL, Garon EB, et al. Phase II study of single-agent navitoclax (ABT-263) and biomarker correlates in patients with relapsed small cell lung cancer. Clin Cancer Res. 2012;18:3163–3169.
130. McDonnell TJ, Troncoso P, Brisbay SM, et al. Expression of the protooncogene bcl-2 in the prostate and its association with emergence of androgen-independent prostate cancer. Cancer Res. 1992;52:6940–6944.
131. Colombel M, Symmans F, Gil S, et al. Detection of the apoptosis-suppressing oncoprotein bc1-2 in hormone-refractory human prostate cancers. Am J Pathol. 1993;143:390–400.
132. Krajewska M, Krajewski S, Epstein JI, et al. Immunohistochemical analysis of bcl-2, bax, bcl-X, and mcl-1 expression in prostate cancers. Am J Pathol. 1996;148:1567–1576.
133. Revelos K, Petraki C, Gregorakis A, et al. Immunohistochemical expression of Bcl2 is an independent predictor of time-to-biochemical failure in patients with clinically localized prostate cancer following radical prostatectomy. Anticancer Res. 2005;25:3123–3133.
134. Yancey D, Nelson KC, Baiz D, et al. BAD dephosphorylation and decreased expression of MCL-1 induce rapid apoptosis in prostate cancer cells. PLoS One. 2013;8:e74561.
135. Leslie NR, Kriplani N, Hermida MA, et al. The PTEN protein:cellular localization and post-translational regulation. Biochem Soc Trans. 2016;44:273–278.
136. Wang Y, Romigh T, He X, et al. Resveratrol regulates the PTEN/AKT pathway through androgen receptor-dependent and -independent mechanisms in prostate cancer cell lines. Hum Mol Genet. 2010;19:4319–4329.
137. Wang Y, Romigh T, He X, et al. Differential regulation of PTEN expression by androgen receptor in prostate and breast cancers. Oncogene. 2011;30:4327–4338.
138. Valiathan RR, Marco M, Leitinger B, et al. Discoidin domain receptor tyrosine kinases:new players in cancer progression. Cancer Metastasis Rev. 2012;31:295–321.
139. Pawson T. Tyrosine kinase signalling pathways. Princess Takamatsu Symp. 1994;24:303–322.
140. Munoz-Moreno L, Bajo AM, Prieto JC, et al. Growth hormone-releasing hormone (GHRH) promotes metastatic phenotypes through EGFR/HER2 transactivation in prostate cancer cells. Mol Cell Endocrinol. 2017;446:59–69.
141. Liu YN, Yin J, Barrett B, et al. Loss of androgen-regulated MicroRNA 1 activates SRC and promotes prostate cancer bone metastasis. Mol Cell Biol. 2015;35:1940–1951.