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Signal transduction pathways in androgen-dependent and -independent prostate cancer cell proliferation.
Endocr Relat Cancer. 2005 Mar; 12(1):119-34.ER

Abstract

In a previous report, we showed that increased activation of Akt, a downstream effector of phosphoinositide 3-kinase (PI3K) together with decreased activation of extracellular-signal-regulated kinase (ERK), a member of the mitogen-activated protein kinase (MAPK) family, predicted poor clinical outcome in prostate cancer (Kreisberg et al. 2004 Cancer Research 64 5232-5236). We now show that Akt activation, but not ERK activation, is correlated with proliferation in human prostate tumors as estimated by the expression of the cell proliferation antigen Ki67. We verified these results in vitro, using the androgen-dependent prostate cancer cell line LNCaP and its androgen-independent clone C4-2 as models of prostate cancer of good and poor clinical outcome, respectively. C4-2 cells expressed higher Akt activation, lower ERK activation and increased proliferation compared with LNCaP cells, similar to cases of poor clinical outcome. The PI3K inhibitor LY294002, but not the MAPK/ERK kinase inhibitor PD98059, induced growth arrest in both cell lines. Transient transfection with constitutively active Akt increased proliferation while dominant negative Akt decreased it, thus showing that Akt plays an important role in prostate cancer proliferation. Akt regulates the expression and activation of the androgen receptor. Androgen receptor inhibition with Casodex induced growth arrest in LNCaP cells, but not in C4-2 cells. Another PI3K downstream effector, p70 S6 kinase, requires prior phosphorylation by mammalian target of rapamycin (mTOR) for complete activation. Activation of p70 S6 kinase was higher in C4-2 compared with LNCaP cells. Rapamycin, an mTOR inhibitor, had a growth-inhibitory effect in C4-2 cells, but not in LNCaP cells. Our data suggest a shift from a Casodex-sensitive proliferation pathway in LNCaP cells to a rapamycin-sensitive pathway in C4-2 cells.

Authors+Show Affiliations

Department of Surgery, University of Texas Health Science Center at San Antonio, 7703 Floyd Curl Drive, San Antonio, TX 78229-3900, USA. ghosh@uthscsaNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Comparative Study
Journal Article
Research Support, Non-U.S. Gov't
Research Support, U.S. Gov't, Non-P.H.S.

Language

eng

PubMed ID

15788644

Citation

Ghosh, Paramita M., et al. "Signal Transduction Pathways in Androgen-dependent and -independent Prostate Cancer Cell Proliferation." Endocrine-related Cancer, vol. 12, no. 1, 2005, pp. 119-34.
Ghosh PM, Malik SN, Bedolla RG, et al. Signal transduction pathways in androgen-dependent and -independent prostate cancer cell proliferation. Endocr Relat Cancer. 2005;12(1):119-34.
Ghosh, P. M., Malik, S. N., Bedolla, R. G., Wang, Y., Mikhailova, M., Prihoda, T. J., Troyer, D. A., & Kreisberg, J. I. (2005). Signal transduction pathways in androgen-dependent and -independent prostate cancer cell proliferation. Endocrine-related Cancer, 12(1), 119-34.
Ghosh PM, et al. Signal Transduction Pathways in Androgen-dependent and -independent Prostate Cancer Cell Proliferation. Endocr Relat Cancer. 2005;12(1):119-34. PubMed PMID: 15788644.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Signal transduction pathways in androgen-dependent and -independent prostate cancer cell proliferation. AU - Ghosh,Paramita M, AU - Malik,Shazli N, AU - Bedolla,Roble G, AU - Wang,Yu, AU - Mikhailova,Margarita, AU - Prihoda,Thomas J, AU - Troyer,Dean A, AU - Kreisberg,Jeffrey I, PY - 2005/3/25/pubmed PY - 2005/7/8/medline PY - 2005/3/25/entrez SP - 119 EP - 34 JF - Endocrine-related cancer JO - Endocr. Relat. Cancer VL - 12 IS - 1 N2 - In a previous report, we showed that increased activation of Akt, a downstream effector of phosphoinositide 3-kinase (PI3K) together with decreased activation of extracellular-signal-regulated kinase (ERK), a member of the mitogen-activated protein kinase (MAPK) family, predicted poor clinical outcome in prostate cancer (Kreisberg et al. 2004 Cancer Research 64 5232-5236). We now show that Akt activation, but not ERK activation, is correlated with proliferation in human prostate tumors as estimated by the expression of the cell proliferation antigen Ki67. We verified these results in vitro, using the androgen-dependent prostate cancer cell line LNCaP and its androgen-independent clone C4-2 as models of prostate cancer of good and poor clinical outcome, respectively. C4-2 cells expressed higher Akt activation, lower ERK activation and increased proliferation compared with LNCaP cells, similar to cases of poor clinical outcome. The PI3K inhibitor LY294002, but not the MAPK/ERK kinase inhibitor PD98059, induced growth arrest in both cell lines. Transient transfection with constitutively active Akt increased proliferation while dominant negative Akt decreased it, thus showing that Akt plays an important role in prostate cancer proliferation. Akt regulates the expression and activation of the androgen receptor. Androgen receptor inhibition with Casodex induced growth arrest in LNCaP cells, but not in C4-2 cells. Another PI3K downstream effector, p70 S6 kinase, requires prior phosphorylation by mammalian target of rapamycin (mTOR) for complete activation. Activation of p70 S6 kinase was higher in C4-2 compared with LNCaP cells. Rapamycin, an mTOR inhibitor, had a growth-inhibitory effect in C4-2 cells, but not in LNCaP cells. Our data suggest a shift from a Casodex-sensitive proliferation pathway in LNCaP cells to a rapamycin-sensitive pathway in C4-2 cells. SN - 1351-0088 UR - https://www.unboundmedicine.com/medline/citation/15788644/Signal_transduction_pathways_in_androgen_dependent_and__independent_prostate_cancer_cell_proliferation_ L2 - https://erc.bioscientifica.com/doi/10.1677/erc.1.00835 DB - PRIME DP - Unbound Medicine ER -