KEGG   PATHWAY: hsa05215Help
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; Cancers
BRITE hierarchy
Pathway map
Prostate cancer
hsa05215

All organismsOrtholog table
Network
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
D00075  
Testosterone (JAN/USP)
D00586  
Flutamide (JP17/USP/INN)
D00961  
Bicalutamide (JAN/USP/INN)
D00965  
Nilutamide (USAN/INN)
D04498  
Idronoxil (USAN/INN)
D10218  
Enzalutamide (JAN/USAN)
D11040  
Apalutamide (JAN/INN)
Organism
Homo sapiens (human) [GN:hsa]
Gene
1027  
CDKN1B; cyclin dependent kinase inhibitor 1B [KO:K06624]
1017  
CDK2; cyclin dependent kinase 2 [KO:K02206] [EC:2.7.11.22]
898  
CCNE1; cyclin E1 [KO:K06626]
9134  
CCNE2; cyclin E2 [KO:K06626]
5925  
RB1; RB transcriptional corepressor 1 [KO:K06618]
1869  
E2F1; E2F transcription factor 1 [KO:K17454]
1870  
E2F2; E2F transcription factor 2 [KO:K09389]
1871  
E2F3; E2F transcription factor 3 [KO:K06620]
7113  
TMPRSS2; transmembrane serine protease 2 [KO:K09633] [EC:3.4.21.-]
2078  
ERG; ERG, ETS transcription factor [KO:K09435]
5328  
PLAU; plasminogen activator, urokinase [KO:K01348] [EC:3.4.21.73]
5327  
PLAT; plasminogen activator, tissue type [KO:K01343] [EC:3.4.21.68]
4314  
MMP3; matrix metallopeptidase 3 [KO:K01394] [EC:3.4.24.17]
4318  
MMP9; matrix metallopeptidase 9 [KO:K01403] [EC:3.4.24.35]
7850  
IL1R2; interleukin 1 receptor type 2 [KO:K04387]
6692  
SPINT1; serine peptidase inhibitor, Kunitz type 1 [KO:K15619]
2119  
ETV5; ETS variant 5 [KO:K15593]
3630  
INS; insulin [KO:K04526]
5154  
PDGFA; platelet derived growth factor subunit A [KO:K04359]
5155  
PDGFB; platelet derived growth factor subunit B [KO:K17386]
56034  
PDGFC; platelet derived growth factor C [KO:K05450]
80310  
PDGFD; platelet derived growth factor D [KO:K05450]
1950  
EGF; epidermal growth factor [KO:K04357]
7039  
TGFA; transforming growth factor alpha [KO:K08774]
3479  
IGF1; insulin like growth factor 1 [KO:K05459]
3645  
INSRR; insulin receptor related receptor [KO:K05086] [EC:2.7.10.1]
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]
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]
1956  
EGFR; epidermal growth factor receptor [KO:K04361] [EC:2.7.10.1]
2064  
ERBB2; erb-b2 receptor tyrosine kinase 2 [KO:K05083] [EC:2.7.10.1]
3480  
IGF1R; insulin like growth factor 1 receptor [KO:K05087] [EC:2.7.10.1]
5290  
PIK3CA; phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha [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]
5291  
PIK3CB; phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit beta [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]
8503  
PIK3R3; phosphoinositide-3-kinase regulatory subunit 3 [KO:K02649]
5728  
PTEN; phosphatase and tensin homolog [KO:K01110] [EC:3.1.3.67 3.1.3.48 3.1.3.16]
5170  
PDPK1; 3-phosphoinositide dependent protein kinase 1 [KO:K06276] [EC:2.7.11.1]
4824  
NKX3-1; NK3 homeobox 1 [KO:K09348]
207  
AKT1; AKT serine/threonine kinase 1 [KO:K04456] [EC:2.7.11.1]
208  
AKT2; AKT serine/threonine kinase 2 [KO:K04456] [EC:2.7.11.1]
10000  
AKT3; AKT serine/threonine kinase 3 [KO:K04456] [EC:2.7.11.1]
842  
CASP9; caspase 9 [KO:K04399] [EC:3.4.22.62]
572  
BAD; BCL2 associated agonist of cell death [KO:K02158]
2308  
FOXO1; forkhead box O1 [KO:K07201]
1026  
CDKN1A; cyclin dependent kinase inhibitor 1A [KO:K06625]
4193  
MDM2; MDM2 proto-oncogene [KO:K06643] [EC:2.3.2.27]
7157  
TP53; tumor protein p53 [KO:K04451]
2932  
GSK3B; glycogen synthase kinase 3 beta [KO:K03083] [EC:2.7.11.26]
1385  
CREB1; cAMP responsive element binding protein 1 [KO:K05870]
468  
ATF4; activating transcription factor 4 [KO:K04374]
10488  
CREB3; cAMP responsive element binding protein 3 [KO:K09048]
90993  
CREB3L1; cAMP responsive element binding protein 3 like 1 [KO:K09048]
64764  
CREB3L2; cAMP responsive element binding protein 3 like 2 [KO:K09048]
84699  
CREB3L3; cAMP responsive element binding protein 3 like 3 [KO:K09048]
148327  
CREB3L4; cAMP responsive element binding protein 3 like 4 [KO:K09048]
9586  
CREB5; cAMP responsive element binding protein 5 [KO:K09047]
1499  
CTNNB1; catenin beta 1 [KO:K02105]
1387  
CREBBP; CREB binding protein [KO:K04498] [EC:2.3.1.48]
2033  
EP300; E1A binding protein p300 [KO:K04498] [EC:2.3.1.48]
6932  
TCF7; transcription factor 7 [KO:K02620]
83439  
TCF7L1; transcription factor 7 like 1 [KO:K04490]
6934  
TCF7L2; transcription factor 7 like 2 [KO:K04491]
51176  
LEF1; lymphoid enhancer binding factor 1 [KO:K04492]
595  
CCND1; cyclin D1 [KO:K04503]
1147  
CHUK; conserved helix-loop-helix ubiquitous kinase [KO:K04467] [EC:2.7.11.10]
3551  
IKBKB; inhibitor of nuclear factor kappa B kinase subunit beta [KO:K07209] [EC:2.7.11.10]
8517  
IKBKG; inhibitor of nuclear factor kappa B kinase subunit gamma [KO:K07210]
4792  
NFKBIA; NFKB inhibitor alpha [KO:K04734]
4790  
NFKB1; nuclear factor kappa B subunit 1 [KO:K02580]
5970  
RELA; RELA proto-oncogene, NF-kB subunit [KO:K04735]
596  
BCL2; BCL2, apoptosis regulator [KO:K02161]
2475  
MTOR; mechanistic target of rapamycin kinase [KO:K07203] [EC:2.7.11.1]
2885  
GRB2; growth factor receptor bound protein 2 [KO:K04364]
6654  
SOS1; SOS Ras/Rac guanine nucleotide exchange factor 1 [KO:K03099]
6655  
SOS2; SOS Ras/Rho guanine nucleotide exchange factor 2 [KO:K03099]
3265  
HRAS; HRas proto-oncogene, GTPase [KO:K02833]
3845  
KRAS; KRAS proto-oncogene, GTPase [KO:K07827]
4893  
NRAS; NRAS proto-oncogene, GTPase [KO:K07828]
369  
ARAF; A-Raf proto-oncogene, serine/threonine kinase [KO:K08845] [EC:2.7.11.1]
673  
BRAF; B-Raf proto-oncogene, serine/threonine kinase [KO:K04365] [EC:2.7.11.1]
5894  
RAF1; Raf-1 proto-oncogene, serine/threonine kinase [KO:K04366] [EC:2.7.11.1]
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]
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]
6716  
SRD5A2; steroid 5 alpha-reductase 2 [KO:K12344] [EC:1.3.1.22]
367  
AR; androgen receptor [KO:K08557]
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]
7184  
HSP90B1; heat shock protein 90 beta family member 1 [KO:K09487]
354  
KLK3; kallikrein related peptidase 3 [KO:K01351] [EC:3.4.21.77]
2950  
GSTP1; glutathione S-transferase pi 1 [KO:K00799] [EC:2.5.1.18]
6935  
ZEB1; zinc finger E-box binding homeobox 1 [KO:K09299]
Compound
C00280  
Androstenedione
C00410  
Progesterone
C00535  
Testosterone
C00735  
Cortisol
C00762  
Cortisone
C00951  
Estradiol-17beta
C01227  
Dehydroepiandrosterone
C03917  
Dihydrotestosterone
C05981  
Phosphatidylinositol-3,4,5-trisphosphate
C07653  
Flutamide
C16038  
2-Amino-1-methyl-6-phenylimidazo[4,5-b]pyridine
Reference
  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
  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
  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
  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
  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
  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
  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
  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
  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
  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
  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
  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
  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
  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
  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
  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 (2016)
DOI:10.18632/oncotarget.11355
KO pathway
 

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