KEGG PATHWAY: ko05215

PATHWAY: ko05215

Entry

ko05215                     Pathway

Name

Prostate cancer

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

ko05215

Prostate cancer

Disease

H00024

Prostate cancer

Orthology

K00922

PIK3CA_B_D; phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha/beta/delta [EC:2.7.1.153]

K01110

PTEN; phosphatidylinositol-3,4,5-trisphosphate 3-phosphatase and dual-specificity protein phosphatase PTEN [EC:3.1.3.16 3.1.3.48 3.1.3.67]

K01343

PLAT; tissue plasminogen activator [EC:3.4.21.68]

K01348

PLAU; urokinase plasminogen activator [EC:3.4.21.73]

K01351

KLK3, PSA; semenogelase [EC:3.4.21.77]

K01394

MMP3; matrix metalloproteinase-3 (stromelysin 1, progelatinase) [EC:3.4.24.17]

K01403

MMP9; matrix metalloproteinase-9 (gelatinase B) [EC:3.4.24.35]

K02105

CTNNB1; catenin beta 1

K02158

BAD; Bcl-2-antagonist of cell death

K02161

BCL2; apoptosis regulator Bcl-2

K02206

CDK2; cyclin-dependent kinase 2 [EC:2.7.11.22]

K02580

NFKB1; nuclear factor NF-kappa-B p105 subunit

K02620

TCF7, TCF-1; transcription factor 7

K02649

PIK3R1_2_3; phosphoinositide-3-kinase regulatory subunit alpha/beta/delta

K02833

HRAS; GTPase HRas

K03083

GSK3B; glycogen synthase kinase 3 beta [EC:2.7.11.26]

K03099

SOS; son of sevenless

K04079

HSP90A, htpG; molecular chaperone HtpG

K04357

EGF; epidermal growth factor

K04359

PDGFA; platelet-derived growth factor subunit A

K04361

EGFR, ERBB1; epidermal growth factor receptor [EC:2.7.10.1]

K04362

FGFR1, CD331; fibroblast growth factor receptor 1 [EC:2.7.10.1]

K04363

PDGFRA, CD140A; platelet-derived growth factor receptor alpha [EC:2.7.10.1]

K04364

GRB2; growth factor receptor-bound protein 2

K04365

BRAF; B-Raf proto-oncogene serine/threonine-protein kinase [EC:2.7.11.1]

K04366

RAF1; RAF proto-oncogene serine/threonine-protein kinase [EC:2.7.11.1]

K04368

MAP2K1, MEK1; mitogen-activated protein kinase kinase 1 [EC:2.7.12.2]

K04369

MAP2K2, MEK2; mitogen-activated protein kinase kinase 2 [EC:2.7.12.2]

K04371

ERK, MAPK1_3; mitogen-activated protein kinase 1/3 [EC:2.7.11.24]

K04374

ATF4, CREB2; cyclic AMP-dependent transcription factor ATF-4

K04387

IL1R2, CD121b; interleukin 1 receptor type II

K04399

CASP9; caspase 9 [EC:3.4.22.62]

K04451

TP53, P53; tumor protein p53

K04456

AKT; RAC serine/threonine-protein kinase [EC:2.7.11.1]

K04467

IKBKA, IKKA, CHUK; inhibitor of nuclear factor kappa-B kinase subunit alpha [EC:2.7.11.10]

K04490

TCF7L1; transcription factor 7-like 1

K04491

TCF7L2; transcription factor 7-like 2

K04492

LEF1; lymphoid enhancer-binding factor 1

K04498

EP300, CREBBP, KAT3; E1A/CREB-binding protein [EC:2.3.1.48]

K04503

CCND1; G1/S-specific cyclin-D1

K04526

INS; insulin

K04603

GRM1; metabotropic glutamate receptor 1

K04604

GRM5; metabotropic glutamate receptor 5

K04734

NFKBIA; NF-kappa-B inhibitor alpha

K04735

RELA; transcription factor p65

K05083

ERBB2, HER2, CD340; receptor tyrosine-protein kinase erbB-2 [EC:2.7.10.1]

K05086

INSRR; insulin receptor-related receptor [EC:2.7.10.1]

K05087

IGF1R, CD221; insulin-like growth factor 1 receptor [EC:2.7.10.1]

K05089

PDGFRB, CD140B; platelet-derived growth factor receptor beta [EC:2.7.10.1]

K05093

FGFR2, CD332; fibroblast growth factor receptor 2 [EC:2.7.10.1]

K05450

PDGFC_D; platelet derived growth factor C/D

K05459

IGF1; insulin-like growth factor 1

K05870

CREB1; cyclic AMP-responsive element-binding protein 1

K06276

PDPK1; 3-phosphoinositide dependent protein kinase-1 [EC:2.7.11.1]

K06618

RB1; retinoblastoma-associated protein

K06620

E2F3; transcription factor E2F3

K06624

CDKN1B, P27, KIP1; cyclin-dependent kinase inhibitor 1B

K06625

CDKN1A, P21, CIP1; cyclin-dependent kinase inhibitor 1A

K06626

CCNE; G1/S-specific cyclin-E1

K06643

MDM2; E3 ubiquitin-protein ligase Mdm2 [EC:2.3.2.27]

K07201

FOXO1; forkhead box protein O1

K07203

MTOR, FRAP, TOR; serine/threonine-protein kinase mTOR [EC:2.7.11.1]

K07209

IKBKB, IKKB; inhibitor of nuclear factor kappa-B kinase subunit beta [EC:2.7.11.10]

K07210

IKBKG, IKKG, NEMO; inhibitor of nuclear factor kappa-B kinase subunit gamma

K07827

KRAS, KRAS2; GTPase KRas

K07828

NRAS; GTPase NRas

K08557

AR, NR3C4; androgen receptor

K08774

TGFA; transforming growth factor, alpha

K08845

ARAF, ARAF1; A-Raf proto-oncogene serine/threonine-protein kinase [EC:2.7.11.1]

K09047

CREB5, CREBPA; cyclic AMP-responsive element-binding protein 5

K09048

CREB3; cyclic AMP-responsive element-binding protein 3

K09299

ZEB1; zinc finger homeobox protein 1

K09348

NKX3-1; homeobox protein Nkx-3.1

K09389

E2F2; transcription factor E2F2

K09435

ERG; transcriptional regulator ERG

K09487

HSP90B, TRA1; heat shock protein 90kDa beta

K09633

TMPRSS2; transmembrane protease serine 2 [EC:3.4.21.122]

K12344

SRD5A2; 3-oxo-5-alpha-steroid 4-dehydrogenase 2 [EC:1.3.1.22]

K13649

FOLR; folate receptor

K14592

FOLH1, GCPII; glutamate carboxypeptidase II (folate hydrolase 1) [EC:3.4.17.21]

K14609

SLC19A1, RFC1; solute carrier family 19 (folate transporter), member 1

K14613

SLC46A1; MFS transporter, PCFT/HCP family, solute carrier family 46 (folate transporter), member 1

K15593

ETV5; ets translocation variant 5

K15619

SPINT1; Kunitz-type protease inhibitor 1

K17386

PDGFB; platelet-derived growth factor subunit B

K17454

E2F1; transcription factor E2F1

K23790

GSTP; glutathione S-transferase P

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