KEGG PATHWAY: hsa05215

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; Cancers

Pathway map

hsa05215

Prostate cancer

Disease

H00024

Prostate cancer

Drug

D00075	Testosterone (JAN/USP)
D00586	Flutamide (JP17/USP/INN)
D00961	Bicalutamide (JAN/USP/INN)
D00965	Nilutamide (USAN/INN)
D03820	Dutasteride (JAN/USAN/INN)
D04498	Idronoxil (USAN/INN)
D10218	Enzalutamide (JAN/USAN)

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]
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 [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]

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

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

KO pathway

ko05215

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Gene (87)   
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