Signal transduction pathways in androgen-dependent and -independent prostate cancer cell proliferation

Paramita M Ghosh, Shazli N. Malik, Roble G. Bedolla, Yu Wang, Margarita Mikhailova, Thomas J. Prihoda, Dean A. Troyer, Jeffrey I. Kreisberg

Research output: Contribution to journalArticle

86 Citations (Scopus)

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 (MARK) 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 transfection000 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.

Original languageEnglish (US)
Pages (from-to)119-134
Number of pages16
JournalEndocrine-Related Cancer
Volume12
Issue number1
DOIs
StatePublished - Mar 2005
Externally publishedYes

Fingerprint

Androgens
Signal Transduction
Prostatic Neoplasms
Cell Proliferation
Extracellular Signal-Regulated MAP Kinases
Sirolimus
1-Phosphatidylinositol 4-Kinase
70-kDa Ribosomal Protein S6 Kinases
Androgen Receptors
Growth
Ki-67 Antigen
Cell Line
2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one
Mitogen-Activated Protein Kinases
Prostate
Neoplasms
Phosphotransferases
Clone Cells
Phosphorylation
Research

ASJC Scopus subject areas

  • Endocrinology
  • Oncology
  • Cancer Research
  • Endocrinology, Diabetes and Metabolism

Cite this

Ghosh, P. M., Malik, S. N., Bedolla, R. G., Wang, Y., Mikhailova, M., Prihoda, T. J., ... Kreisberg, J. I. (2005). Signal transduction pathways in androgen-dependent and -independent prostate cancer cell proliferation. Endocrine-Related Cancer, 12(1), 119-134. https://doi.org/10.1677/erc.1.00835

Signal transduction pathways in androgen-dependent and -independent prostate cancer cell proliferation. / Ghosh, Paramita M; Malik, Shazli N.; Bedolla, Roble G.; Wang, Yu; Mikhailova, Margarita; Prihoda, Thomas J.; Troyer, Dean A.; Kreisberg, Jeffrey I.

In: Endocrine-Related Cancer, Vol. 12, No. 1, 03.2005, p. 119-134.

Research output: Contribution to journalArticle

Ghosh, PM, Malik, SN, Bedolla, RG, Wang, Y, Mikhailova, M, Prihoda, TJ, Troyer, DA & Kreisberg, JI 2005, 'Signal transduction pathways in androgen-dependent and -independent prostate cancer cell proliferation', Endocrine-Related Cancer, vol. 12, no. 1, pp. 119-134. https://doi.org/10.1677/erc.1.00835
Ghosh, Paramita M ; Malik, Shazli N. ; Bedolla, Roble G. ; Wang, Yu ; Mikhailova, Margarita ; Prihoda, Thomas J. ; Troyer, Dean A. ; Kreisberg, Jeffrey I. / Signal transduction pathways in androgen-dependent and -independent prostate cancer cell proliferation. In: Endocrine-Related Cancer. 2005 ; Vol. 12, No. 1. pp. 119-134.
@article{0d14f0b3b0cf4bfdadb6668bab6c50a1,
title = "Signal transduction pathways in androgen-dependent and -independent prostate cancer cell proliferation",
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 (MARK) 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 transfection000 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.",
author = "Ghosh, {Paramita M} and Malik, {Shazli N.} and Bedolla, {Roble G.} and Yu Wang and Margarita Mikhailova and Prihoda, {Thomas J.} and Troyer, {Dean A.} and Kreisberg, {Jeffrey I.}",
year = "2005",
month = "3",
doi = "10.1677/erc.1.00835",
language = "English (US)",
volume = "12",
pages = "119--134",
journal = "Endocrine-Related Cancer",
issn = "1351-0088",
publisher = "Society for Endocrinology",
number = "1",

}

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

Y1 - 2005/3

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 (MARK) 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 transfection000 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.

AB - 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 (MARK) 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 transfection000 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.

UR - http://www.scopus.com/inward/record.url?scp=16444377912&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=16444377912&partnerID=8YFLogxK

U2 - 10.1677/erc.1.00835

DO - 10.1677/erc.1.00835

M3 - Article

C2 - 15788644

AN - SCOPUS:16444377912

VL - 12

SP - 119

EP - 134

JO - Endocrine-Related Cancer

JF - Endocrine-Related Cancer

SN - 1351-0088

IS - 1

ER -