KEGG   PATHWAY: hsa05215
Entry
hsa05215                    Pathway                                
Name
Prostate cancer - Homo sapiens (human)
Description
Prostate cancer constitutes a major health problem in Western countries. It is the most frequently diagnosed cancer among men and the second leading cause of male cancer deaths. The identification of key molecular alterations in prostate-cancer cells implicates carcinogen defenses (GSTP1), growth-factor-signaling pathways (NKX3.1, PTEN, and p27), and androgens (AR) as critical determinants of the phenotype of prostate-cancer cells. Glutathione S-transferases (GSTP1) are detoxifying enzymes. Cells of prostatic intraepithelial neoplasia, devoid of GSTP1, undergo genomic damage mediated by carcinogens. NKX3.1, PTEN, and p27 regulate the growth and survival of prostate cells in the normal prostate. Inadequate levels of PTEN and NKX3.1 lead to a reduction in p27 levels and to increased proliferation and decreased apoptosis. Androgen receptor (AR) is a transcription factor that is normally activated by its androgen ligand. During androgen withdrawal therapy, the AR signal transduction pathway also could be activated by amplification of the AR gene, by AR gene mutations, or by altered activity of AR coactivators. Through these mechanisms, tumor cells lead to the emergence of androgen-independent prostate cancer.
Class
Human Diseases; Cancer: specific types
Pathway map
hsa05215  Prostate cancer
hsa05215

Network
nt06214  PI3K signaling (cancer)
nt06227  Nuclear receptor signaling (cancer)
nt06230  Cell cycle (cancer)
nt06263  Hepatocellular carcinoma
nt06267  Small cell lung cancer
nt06268  Melanoma
nt06270  Breast cancer
nt06271  Endometrial cancer
nt06272  Prostate cancer
nt06273  Glioma
  Element
N00052  Mutation-inactivated PTEN to PI3K signaling pathway
N00082  Loss of NKX3-1 to PI3K signaling pathway
N00084  Amplified AR to androgen receptor signaling pathway
N00085  Mutation-activated AR to androgen receptor signaling pathway
N00093  Loss of CDKN1B to p27-cell cycle G1/S
Disease
H00024  Prostate cancer
Drug
D00586  Flutamide (JP18/USP/INN)
D00961  Bicalutamide (JP18/USP/INN)
D00965  Nilutamide (USAN/INN)
D01299  Chlormadinone acetate (JP18/USAN)
D03372  Capromab pendetide (USAN)
D04525  Indium In 111 capromab pendetide (USP)
D10070  Iofolastat I 123 (USAN)
D10218  Enzalutamide (JAN/USAN)
D11040  Apalutamide (JAN/INN)
D11045  Darolutamide (JAN/USAN/INN)
D12121  Acapatamab (USAN)
D12132  Piflufolastat F-18 (USAN)
D12257  Gallium Ga 68 gozetotide (USAN)
D12335  Lutetium Lu 177 vipivotide tetraxetan (USAN)
D12566  Nezastomig (USAN)
D12606  Flotufolastat F18 gallium (USAN)
D13129  Abefolastat tesaroxetan (USAN/INN)
Organism
Homo sapiens (human) [GN:hsa]
Gene
10000  AKT3; AKT serine/threonine kinase 3 [KO:K04456] [EC:2.7.11.1]
1017  CDK2; cyclin dependent kinase 2 [KO:K02206] [EC:2.7.11.22]
1026  CDKN1A; cyclin dependent kinase inhibitor 1A [KO:K06625]
1027  CDKN1B; cyclin dependent kinase inhibitor 1B [KO:K06624]
10488  CREB3; cAMP responsive element binding protein 3 [KO:K09048]
110117499  P3R3URF-PIK3R3; P3R3URF-PIK3R3 readthrough [KO:K02649]
113235  SLC46A1; solute carrier family 46 member 1 [KO:K14613]
1147  CHUK; component of inhibitor of nuclear factor kappa B kinase complex [KO:K04467] [EC:2.7.11.10]
1385  CREB1; cAMP responsive element binding protein 1 [KO:K05870]
1387  CREBBP; CREB binding lysine acetyltransferase [KO:K04498] [EC:2.3.1.48]
148327  CREB3L4; cAMP responsive element binding protein 3 like 4 [KO:K09048]
1499  CTNNB1; catenin beta 1 [KO:K02105]
1869  E2F1; E2F transcription factor 1 [KO:K17454]
1870  E2F2; E2F transcription factor 2 [KO:K09389]
1871  E2F3; E2F transcription factor 3 [KO:K06620]
1950  EGF; epidermal growth factor [KO:K04357]
1956  EGFR; epidermal growth factor receptor [KO:K04361] [EC:2.7.10.1]
2033  EP300; EP300 lysine acetyltransferase [KO:K04498] [EC:2.3.1.48]
2064  ERBB2; erb-b2 receptor tyrosine kinase 2 [KO:K05083] [EC:2.7.10.1]
207  AKT1; AKT serine/threonine kinase 1 [KO:K04456] [EC:2.7.11.1]
2078  ERG; ETS transcription factor ERG [KO:K09435]
208  AKT2; AKT serine/threonine kinase 2 [KO:K04456] [EC:2.7.11.1]
2119  ETV5; ETS variant transcription factor 5 [KO:K15593]
2260  FGFR1; fibroblast growth factor receptor 1 [KO:K04362] [EC:2.7.10.1]
2263  FGFR2; fibroblast growth factor receptor 2 [KO:K05093] [EC:2.7.10.1]
2308  FOXO1; forkhead box O1 [KO:K07201]
2346  FOLH1; folate hydrolase 1 [KO:K14592] [EC:3.4.17.21]
2348  FOLR1; folate receptor alpha [KO:K13649]
2350  FOLR2; folate receptor beta [KO:K13649]
2352  FOLR3; folate receptor gamma [KO:K13649]
2475  MTOR; mechanistic target of rapamycin kinase [KO:K07203] [EC:2.7.11.1]
2885  GRB2; growth factor receptor bound protein 2 [KO:K04364]
2911  GRM1; glutamate metabotropic receptor 1 [KO:K04603]
2915  GRM5; glutamate metabotropic receptor 5 [KO:K04604]
2932  GSK3B; glycogen synthase kinase 3 beta [KO:K03083] [EC:2.7.11.26]
2950  GSTP1; glutathione S-transferase pi 1 [KO:K23790]
3265  HRAS; HRas proto-oncogene, GTPase [KO:K02833]
3320  HSP90AA1; heat shock protein 90 alpha family class A member 1 [KO:K04079]
3326  HSP90AB1; heat shock protein 90 alpha family class B member 1 [KO:K04079]
3479  IGF1; insulin like growth factor 1 [KO:K05459]
3480  IGF1R; insulin like growth factor 1 receptor [KO:K05087] [EC:2.7.10.1]
354  KLK3; kallikrein related peptidase 3 [KO:K01351] [EC:3.4.21.77]
3551  IKBKB; inhibitor of nuclear factor kappa B kinase subunit beta [KO:K07209] [EC:2.7.11.10]
3630  INS; insulin [KO:K04526]
3645  INSRR; insulin receptor related receptor [KO:K05086] [EC:2.7.10.1]
367  AR; androgen receptor [KO:K08557]
369  ARAF; A-Raf proto-oncogene, serine/threonine kinase [KO:K08845] [EC:2.7.11.1]
3845  KRAS; KRAS proto-oncogene, GTPase [KO:K07827]
4193  MDM2; MDM2 proto-oncogene [KO:K06643] [EC:2.3.2.27]
4314  MMP3; matrix metallopeptidase 3 [KO:K01394] [EC:3.4.24.17]
4318  MMP9; matrix metallopeptidase 9 [KO:K01403] [EC:3.4.24.35]
468  ATF4; activating transcription factor 4 [KO:K04374]
4790  NFKB1; nuclear factor kappa B subunit 1 [KO:K02580]
4792  NFKBIA; NFKB inhibitor alpha [KO:K04734]
4824  NKX3-1; NK3 homeobox 1 [KO:K09348]
4893  NRAS; NRAS proto-oncogene, GTPase [KO:K07828]
51176  LEF1; lymphoid enhancer binding factor 1 [KO:K04492]
5154  PDGFA; platelet derived growth factor subunit A [KO:K04359]
5155  PDGFB; platelet derived growth factor subunit B [KO:K17386]
5156  PDGFRA; platelet derived growth factor receptor alpha [KO:K04363] [EC:2.7.10.1]
5159  PDGFRB; platelet derived growth factor receptor beta [KO:K05089] [EC:2.7.10.1]
5170  PDPK1; 3-phosphoinositide dependent protein kinase 1 [KO:K06276] [EC:2.7.11.1]
5290  PIK3CA; phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha [KO:K00922] [EC:2.7.1.153]
5291  PIK3CB; phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit beta [KO:K00922] [EC:2.7.1.153]
5293  PIK3CD; phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit delta [KO:K00922] [EC:2.7.1.153]
5295  PIK3R1; phosphoinositide-3-kinase regulatory subunit 1 [KO:K02649]
5296  PIK3R2; phosphoinositide-3-kinase regulatory subunit 2 [KO:K02649]
5327  PLAT; plasminogen activator, tissue type [KO:K01343] [EC:3.4.21.68]
5328  PLAU; plasminogen activator, urokinase [KO:K01348] [EC:3.4.21.73]
5594  MAPK1; mitogen-activated protein kinase 1 [KO:K04371] [EC:2.7.11.24]
5595  MAPK3; mitogen-activated protein kinase 3 [KO:K04371] [EC:2.7.11.24]
56034  PDGFC; platelet derived growth factor C [KO:K05450]
5604  MAP2K1; mitogen-activated protein kinase kinase 1 [KO:K04368] [EC:2.7.12.2]
5605  MAP2K2; mitogen-activated protein kinase kinase 2 [KO:K04369] [EC:2.7.12.2]
572  BAD; BCL2 associated agonist of cell death [KO:K02158]
5728  PTEN; phosphatase and tensin homolog [KO:K01110] [EC:3.1.3.16 3.1.3.48 3.1.3.67]
5894  RAF1; Raf-1 proto-oncogene, serine/threonine kinase [KO:K04366] [EC:2.7.11.1]
5925  RB1; RB transcriptional corepressor 1 [KO:K06618]
595  CCND1; cyclin D1 [KO:K04503]
596  BCL2; BCL2 apoptosis regulator [KO:K02161]
5970  RELA; RELA proto-oncogene, NF-kB subunit [KO:K04735]
64764  CREB3L2; cAMP responsive element binding protein 3 like 2 [KO:K09048]
6573  SLC19A1; solute carrier family 19 member 1 [KO:K14609]
6654  SOS1; SOS Ras/Rac guanine nucleotide exchange factor 1 [KO:K03099]
6655  SOS2; SOS Ras/Rho guanine nucleotide exchange factor 2 [KO:K03099]
6692  SPINT1; serine peptidase inhibitor, Kunitz type 1 [KO:K15619]
6716  SRD5A2; steroid 5 alpha-reductase 2 [KO:K12344] [EC:1.3.1.22]
673  BRAF; B-Raf proto-oncogene, serine/threonine kinase [KO:K04365] [EC:2.7.11.1]
6932  TCF7; transcription factor 7 [KO:K02620]
6934  TCF7L2; transcription factor 7 like 2 [KO:K04491]
6935  ZEB1; zinc finger E-box binding homeobox 1 [KO:K09299]
7039  TGFA; transforming growth factor alpha [KO:K08774]
7113  TMPRSS2; transmembrane serine protease 2 [KO:K09633] [EC:3.4.21.122]
7157  TP53; tumor protein p53 [KO:K04451]
7184  HSP90B1; heat shock protein 90 beta family member 1 [KO:K09487]
7850  IL1R2; interleukin 1 receptor type 2 [KO:K04387]
80310  PDGFD; platelet derived growth factor D [KO:K05450]
83439  TCF7L1; transcription factor 7 like 1 [KO:K04490]
842  CASP9; caspase 9 [KO:K04399] [EC:3.4.22.62]
84699  CREB3L3; cAMP responsive element binding protein 3 like 3 [KO:K09048]
8503  PIK3R3; phosphoinositide-3-kinase regulatory subunit 3 [KO:K02649]
8517  IKBKG; inhibitor of nuclear factor kappa B kinase regulatory subunit gamma [KO:K07210]
898  CCNE1; cyclin E1 [KO:K06626]
90993  CREB3L1; cAMP responsive element binding protein 3 like 1 [KO:K09048]
9134  CCNE2; cyclin E2 [KO:K06626]
9586  CREB5; cAMP responsive element binding protein 5 [KO:K09047]
Compound
C00025  L-Glutamate
C00280  Androstenedione
C00410  Progesterone
C00504  Folate
C00535  Testosterone
C00735  Cortisol
C00762  Cortisone
C00951  Estradiol-17beta
C01042  N-Acetyl-L-aspartate
C01227  Dehydroepiandrosterone
C03917  Dihydrotestosterone
C05981  Phosphatidylinositol-3,4,5-trisphosphate
C07653  Flutamide
C12270  N-Acetylaspartylglutamate
C16038  2-Amino-1-methyl-6-phenylimidazo[4,5-b]pyridine
Reference
PMID:12878745
  Authors
Nelson WG, De Marzo AM, Isaacs WB.
  Title
Prostate cancer.
  Journal
N Engl J Med 349:366-81 (2003)
DOI:10.1056/NEJMra021562
Reference
PMID:15724144
  Authors
Li L, Ittmann MM, Ayala G, Tsai MJ, Amato RJ, Wheeler TM, Miles BJ, Kadmon D, Thompson TC.
  Title
The emerging role of the PI3-K-Akt pathway in prostate cancer progression.
  Journal
Prostate Cancer Prostatic Dis 8:108-18 (2005)
DOI:10.1038/sj.pcan.4500776
Reference
PMID:16551847
  Authors
Pienta KJ, Bradley D.
  Title
Mechanisms underlying the development of androgen-independent prostate cancer.
  Journal
Clin Cancer Res 12:1665-71 (2006)
DOI:10.1158/1078-0432.CCR-06-0067
Reference
PMID:11900250
  Authors
Feldman BJ, Feldman D.
  Title
The development of androgen-independent prostate cancer.
  Journal
Nat Rev Cancer 1:34-45 (2001)
DOI:10.1038/35094009
Reference
PMID:15082523
  Authors
Heinlein CA, Chang C.
  Title
Androgen receptor in prostate cancer.
  Journal
Endocr Rev 25:276-308 (2004)
DOI:10.1210/er.2002-0032
Reference
PMID:9422516
  Authors
Koivisto P, Kolmer M, Visakorpi T, Kallioniemi OP.
  Title
Androgen receptor gene and hormonal therapy failure of prostate cancer.
  Journal
Am J Pathol 152:1-9 (1998)
Reference
PMID:10835690
  Authors
Zhao XY, Malloy PJ, Krishnan AV, Swami S, Navone NM, Peehl DM, Feldman D.
  Title
Glucocorticoids can promote androgen-independent growth of prostate cancer cells through a mutated androgen receptor.
  Journal
Nat Med 6:703-6 (2000)
DOI:10.1038/76287
Reference
PMID:10453277
  Authors
Macri E, Loda M.
  Title
Role of p27 in prostate carcinogenesis.
  Journal
Cancer Metastasis Rev 17:337-44 (1998)
DOI:10.1023/A:1006133620914
Reference
PMID:11750244
  Authors
Steers WD.
  Title
5alpha-reductase activity in the prostate.
  Journal
Urology 58:17-24; discussion 24 (2001)
DOI:10.1016/S0090-4295(01)01299-7
Reference
PMID:8069858
  Authors
Lin D, Meyer DJ, Ketterer B, Lang NP, Kadlubar FF.
  Title
Effects of human and rat glutathione S-transferases on the covalent DNA binding of the N-acetoxy derivatives of heterocyclic amine carcinogens in vitro: a possible mechanism of organ specificity in their carcinogenesis.
  Journal
Cancer Res 54:4920-6 (1994)
Reference
PMID:11527574
  Authors
Grimes CA, Jope RS.
  Title
The multifaceted roles of glycogen synthase kinase 3beta in cellular signaling.
  Journal
Prog Neurobiol 65:391-426 (2001)
DOI:10.1016/S0301-0082(01)00011-9
Reference
PMID:21747944
  Authors
Leshem O, Madar S, Kogan-Sakin I, Kamer I, Goldstein I, Brosh R, Cohen Y, Jacob-Hirsch J, Ehrlich M, Ben-Sasson S, Goldfinger N, Loewenthal R, Gazit E, Rotter V, Berger R
  Title
TMPRSS2/ERG promotes epithelial to mesenchymal transition through the ZEB1/ZEB2 axis in a prostate cancer model.
  Journal
PLoS One 6:e21650 (2011)
DOI:10.1371/journal.pone.0021650
Reference
PMID:20478527
  Authors
Yu J, Yu J, Mani RS, Cao Q, Brenner CJ, Cao X, Wang X, Wu L, Li J, Hu M, Gong Y, Cheng H, Laxman B, Vellaichamy A, Shankar S, Li Y, Dhanasekaran SM, Morey R, Barrette T, Lonigro RJ, Tomlins SA, Varambally S, Qin ZS, Chinnaiyan AM
  Title
An integrated network of androgen receptor, polycomb, and TMPRSS2-ERG gene fusions in prostate cancer progression.
  Journal
Cancer Cell 17:443-54 (2010)
DOI:10.1016/j.ccr.2010.03.018
Reference
PMID:19399032
  Authors
Squire JA
  Title
TMPRSS2-ERG and PTEN loss in prostate cancer.
  Journal
Nat Genet 41:509-10 (2009)
DOI:10.1038/ng0509-509
Reference
PMID:25915839
  Authors
Adamo P, Ladomery MR
  Title
The oncogene ERG: a key factor in prostate cancer.
  Journal
Oncogene 35:403-14 (2016)
DOI:10.1038/onc.2015.109
Reference
PMID:25485532
  Authors
Burdova A, Bouchal J, Tavandzis S, Kolar Z
  Title
TMPRSS2-ERG gene fusion in prostate cancer.
  Journal
Biomed Pap Med Fac Univ Palacky Olomouc Czech Repub 158:502-10 (2014)
DOI:10.5507/bp.2014.065
Reference
PMID:18172298
  Authors
Helgeson BE, Tomlins SA, Shah N, Laxman B, Cao Q, Prensner JR, Cao X, Singla N, Montie JE, Varambally S, Mehra R, Chinnaiyan AM
  Title
Characterization of TMPRSS2:ETV5 and SLC45A3:ETV5 gene fusions in prostate cancer.
  Journal
Cancer Res 68:73-80 (2008)
DOI:10.1158/0008-5472.CAN-07-5352
Reference
PMID:28968951
  Authors
Kim H, Datta A, Talwar S, Saleem SN, Mondal D, Abdel-Mageed AB
  Title
Estradiol-ERbeta2 signaling axis confers growth and migration of CRPC cells through TMPRSS2-ETV5 gene fusion.
  Journal
Oncotarget 8:62820-62833 (2017)
DOI:10.18632/oncotarget.11355
Reference
PMID:38977769
  Authors
Bakht MK, Beltran H
  Title
Biological determinants of PSMA expression, regulation and heterogeneity in prostate cancer.
  Journal
Nat Rev Urol 22:26-45 (2025)
DOI:10.1038/s41585-024-00900-z
Related
pathway
hsa00140  Steroid hormone biosynthesis
hsa04010  MAPK signaling pathway
hsa04060  Cytokine-cytokine receptor interaction
hsa04110  Cell cycle
hsa04115  p53 signaling pathway
hsa04151  PI3K-Akt signaling pathway
hsa04210  Apoptosis
hsa04981  Folate transport and metabolism
hsa05202  Transcriptional misregulation in cancer
KO pathway
ko05215   

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