Phosphatidylinositol 3-Kinase/Akt Stimulates Androgen Pathway through GSK3β Inhibition and Nuclear β-Catenin Accumulation

Abstract

PI3K/Akt plays a critical role in prostate cancer cell growth and survival. Recent studies have shown that the effect of PI3K/Akt in prostate cells is mediated through androgen signaling. The PI3K inhibitor, LY294002, and a tumor suppressor, PTEN, negatively regulate the PI3K/Akt pathway and repress AR activity. However, the molecular mechanisms whereby PI3K/Akt and PTEN regulate the androgen pathway are currently unclear. Here, we demonstrate that blocking the PI3K/Akt pathway reduces the expression of an endogenous AR target gene. Moreover, we show that the repression of AR activity by LY294002 is mediated through phosphorylation and inactivation of GSK3β, a downstream substrate of PI3K/Akt, which results in the nuclear accumulation of β-catenin. Given the recent evidence that β-catenin acts as a coactivator of AR, our findings suggest a novel mechanism by which PI3K/Akt modulates androgen signaling. In a PTEN-null prostate cancer cell line, we show that PTEN expression reduces β-catenin-mediated augmentation of AR transactivation. Using the mutants of β-catenin, we further demonstrate that the repressive effect of PTEN is mediated by a GSK3β-regulated degradation of β-catenin. Our results delineate a novel link among the PI3K, wnt, and androgen pathways and provide fresh insights into the mechanisms of prostate tumor development and progression. PI3K/Akt plays a critical role in prostate cancer cell growth and survival. Recent studies have shown that the effect of PI3K/Akt in prostate cells is mediated through androgen signaling. The PI3K inhibitor, LY294002, and a tumor suppressor, PTEN, negatively regulate the PI3K/Akt pathway and repress AR activity. However, the molecular mechanisms whereby PI3K/Akt and PTEN regulate the androgen pathway are currently unclear. Here, we demonstrate that blocking the PI3K/Akt pathway reduces the expression of an endogenous AR target gene. Moreover, we show that the repression of AR activity by LY294002 is mediated through phosphorylation and inactivation of GSK3β, a downstream substrate of PI3K/Akt, which results in the nuclear accumulation of β-catenin. Given the recent evidence that β-catenin acts as a coactivator of AR, our findings suggest a novel mechanism by which PI3K/Akt modulates androgen signaling. In a PTEN-null prostate cancer cell line, we show that PTEN expression reduces β-catenin-mediated augmentation of AR transactivation. Using the mutants of β-catenin, we further demonstrate that the repressive effect of PTEN is mediated by a GSK3β-regulated degradation of β-catenin. Our results delineate a novel link among the PI3K, wnt, and androgen pathways and provide fresh insights into the mechanisms of prostate tumor development and progression. androgen receptor phosphatidylinositol 3,4,5-trisphosphate glycogen synthase kinase 3β phosphatase and tensin homolog deleted on chromosome 10 dihydrotestosterone prostate-specific antigen Prostate cancer is the most common malignancy in men and the second leading cause of cancer death in the United States (1Landis S.H. Murray T. Bolden S. Wingo P.A. CA-Cancer J. Clin. 1999; 49: 8-31Crossref PubMed Scopus (3127) Google Scholar). The fact that androgen ablation is an effective treatment for the majority of prostate cancers indicates that androgen plays an essential role in regulating the growth of prostate cancer cells (2Kyprianou N. Isaacs J.T. Endocrinology. 1988; 122: 552-562Crossref PubMed Scopus (633) Google Scholar, 3Isaacs J.T. Kyprianou N. Cancer Treat. Res. 1989; 46: 177-193Crossref PubMed Scopus (4) Google Scholar). The growth-promoting effects of androgen in prostate cells are mediated mostly through the androgen receptor (AR).1 The AR belongs to the nuclear receptor superfamily and acts as a ligand-dependent transcription factor (4Chang C.S. Kokontis J. Liao S.T. Science. 1988; 240: 324-326Crossref PubMed Scopus (724) Google Scholar, 5Tsai M.J. O'Malley B.W. Annu. Rev. Biochem. 1994; 63: 451-486Crossref PubMed Scopus (2678) Google Scholar). Recent studies suggest that other signal transduction pathways can modulate AR activity and that they may also contribute to the development and progression of prostate cancer (6Jenster G. Semin. Oncol. 1999; 26: 407-421PubMed Google Scholar, 7Hayes S.A. Zarnegar M. Sharma M. Yang F. Peehl D.M. ten Dijke P. Sun Z. Cancer Res. 2001; 61: 2112-2118PubMed Google Scholar).The phosphatidylinositol 3-kinase (PI3K) consists of regulatory (p85) and catalytic (p110) subunits that participate in multiple cellular processes including cell growth, transformation, differentiation, and survival (8Carpenter C.L. Cantley L.C. Curr. Opin. Cell Biol. 1996; 8: 153-158Crossref PubMed Scopus (575) Google Scholar). An oncoprotein, Akt/PKB, has been identified as a key effector of the PI3K signaling pathway (9Datta S.R. Dudek H. Tao X. Masters S., Fu, H. Gotoh Y. Greenberg M.E. Cell. 1997; 91: 231-241Abstract Full Text Full Text PDF PubMed Scopus (4914) Google Scholar, 10Kauffmann-Zeh A. Rodriguez-Viciana P. Ulrich E. Gilbert C. Coffer P. Downward J. Evan G. Nature. 1997; 385: 544-548Crossref PubMed Scopus (1068) Google Scholar). The binding of PI3K-generated phospholipids to Akt results in the translocation of Akt from the cytoplasm to the inner surface of the plasma membrane where Akt is phosphorylated by the upstream kinases, PDK-1, PDK-2, and ILK (11Andjelkovic M. Jakubowicz T. Cron P. Ming X.F. Han J.W. Hemmings B.A. Proc. Natl. Acad. Sci. U. S. A. 1996; 93: 5699-5704Crossref PubMed Scopus (427) Google Scholar, 12Franke T.F. Kaplan D.R. Cantley L.C. Cell. 1997; 88: 435-437Abstract Full Text Full Text PDF PubMed Scopus (1513) Google Scholar). The activation of Akt results in the phosphorylation of a number of downstream substrates such as glycogen synthase kinase (GSK3), Bad, and caspase9 and the forkhead transcription factors, Raf, Iκb kinase, and phosphodiesterase 3B (13Datta S.R. Brunet A. Greenberg M.E. Genes Dev. 1999; 13: 2905-2927Crossref PubMed Scopus (3707) Google Scholar). As one of the principal physiological substrates of Akt, GSK3 is a ubiquitously expressed protein serine/threonine kinase that was initially identified as an that glycogen in to D.R. P. M. Hemmings B.A. Nature. PubMed Scopus Google Scholar, Biochem. J. 1994; PubMed Scopus Google Scholar). has been shown that plays an role in the pathway by regulating the degradation of β-catenin J. N. Y. Acad. Sci. PubMed Scopus Google Scholar, C. J. Biol. 1997; Full Text Full Text PDF PubMed Scopus Google plays a role in cell and in the signaling pathway P. Genes Dev. PubMed Google Scholar). to in β-catenin is to cellular of the β-catenin is in the cell membrane where is the of a protein in M. H. J. 1989; 8: PubMed Scopus Google Scholar). of β-catenin is in the and cytoplasm where signaling. In the of a β-catenin is by a GSK3β, and the tumor the phosphorylation of and in the of β-catenin and target for degradation by the pathway H. A. J. A. J. 1997; PubMed Scopus Google Scholar). signaling which to an accumulation of β-catenin in the and the of of the M. M. M. J. S. J. H. Cell. 1996; Full Text Full Text PDF PubMed Scopus Google and other transcription S. Cancer Res. Google X. Sharma M. Sun Z. J. Biol. Full Text Full Text PDF PubMed Scopus Google Scholar).The tumor PTEN is a phosphatase L.C. Proc. Natl. Acad. Sci. U. S. A. 1999; PubMed Scopus Google Scholar). studies that of PTEN is a common in a of including prostate cancer J. C. S. J. C. S.H. M. H. Science. 1997; PubMed Scopus Google Scholar). PTEN was to in prostate prostate and in prostate cancer cell J. C. S. J. C. S.H. M. H. Science. 1997; PubMed Scopus Google Scholar, P.A. S.A. H. T. T. 1997; PubMed Scopus Google Scholar). In the expression of PTEN protein as as Akt activity has been in X. C.L. Proc. Natl. Acad. Sci. U. S. A. PubMed Scopus Google Scholar). has been shown that PTEN cell growth and transcription in prostate cancer cells P. J. Biol. 2001; Full Text Full Text PDF PubMed Scopus Google has been shown to prostate cancer cell survival and growth PTEN and the PI3K LY294002 negatively regulate P. J. Biol. 2001; Full Text Full Text PDF PubMed Scopus Google Scholar, G. Cancer Res. Google Scholar). mechanisms have been for the molecular by which and PTEN regulate transcription is currently unclear. a β-catenin and AR was identified by and S. Cancer Res. Google Scholar, X. Sharma M. Sun Z. J. Biol. Full Text Full Text PDF PubMed Scopus Google Scholar). β-catenin the ligand-dependent activity of AR in prostate cancer Here, we provide multiple of evidence that the the androgen and PI3K/Akt pathways is mediated through the of the PI3K/Akt downstream effector inactivation by phosphorylation results in nuclear of β-catenin, which AR activity. findings delineate a novel mechanism by which PI3K/Akt and PTEN regulate the androgen pathway prostate cell growth and pathway plays a critical role in prostate cell and survival L.C. Proc. Natl. Acad. Sci. U. S. A. 1999; PubMed Scopus Google Scholar). PTEN, which is in prostate cancer negatively by blocking the PI3K/Akt of evidence that PI3K/Akt and PTEN can modulate cell growth and transcription in prostate cancer cells P. J. Biol. 2001; Full Text Full Text PDF PubMed Scopus Google Scholar, G. Cancer Res. Google a link the PI3K/Akt and androgen In we that β-catenin acts as the of for the the PI3K/Akt and androgen signaling The are is the degradation of β-catenin by GSK3β, a downstream effector of PI3K/Akt, and our recent that β-catenin AR and ligand-dependent transcription X. Sharma M. Sun Z. J. Biol. Full Text Full Text PDF PubMed Scopus Google Scholar).The of β-catenin expression and signaling is as in the of of including prostate cancer P. Genes Dev. PubMed Google Scholar, Cancer Res. Google Scholar). cells of cellular β-catenin by in the of the by regulatory in β-catenin other signaling pathways are also in regulating cellular β-catenin Proc. Natl. Acad. Sci. U. S. A. PubMed Scopus Google Scholar, C. A. M.J. F. G. C. J. 2001; PubMed Scopus Google Scholar, D.M. J. 2001; PubMed Scopus Google Scholar). In we that PI3K/Akt the of nuclear β-catenin by phosphorylation and inactivation of the downstream substrate in prostate cancer Given that β-catenin acts as a coactivator of AR, provide evidence to suggest a mechanism whereby PI3K/Akt can prostate cell and survival through androgen studies that PTEN negatively the PI3K/Akt pathway in prostate cancer cells P. J. Biol. 2001; Full Text Full Text PDF PubMed Scopus Google Scholar). The expression of PTEN in a PTEN-null prostate cancer cell line, cell growth and In we that the of PTEN in reduces β-catenin-mediated augmentation of AR PTEN effect in cells β-catenin mutants a the phosphorylation The results from our further that PTEN reduces the nuclear accumulation of β-catenin in prostate the β-catenin mutants in our are to degradation by the we that the of β-catenin by PTEN is mediated through Our results are a recent that nuclear β-catenin protein is in PTEN and expression can the of PTEN S. S. J. Cell Biol. 2001; PubMed Scopus Google Scholar). The also that PTEN negatively the PI3K pathway by phosphorylation of In the PTEN as a PI3K are our the effects mediated by the PI3K of the AR protein such as by phosphorylation has been to an mechanism for AR activity in prostate cancer cells M. C. J. J. Biol. Full Text Full Text PDF PubMed Scopus Google Scholar, Res. 1996; PubMed Scopus Google Scholar, T. N. J. Biol. Full Text Full Text PDF PubMed Scopus Google Scholar). The for Akt phosphorylation identified in the and the binding of AR G. Cancer Res. Google Scholar). that Akt can to and AR G. Cancer Res. Google Scholar). However, and we to show a Akt and AR the phosphorylation of AR by Akt in to also by P. J. Biol. 2001; Full Text Full Text PDF PubMed Scopus Google Scholar). results may to the of and they also suggest that other pathways may in As in we a novel molecular mechanism for PI3K/Akt and PTEN of androgen signaling in prostate cancer role of β-catenin in has been the transcription Curr. Opin. Cell Biol. 1999; PubMed Scopus Google Scholar). as we and have X. Sharma M. Sun Z. J. Biol. Full Text Full Text PDF PubMed Scopus Google Scholar, G. 2001; β-catenin is shown to have effect on the activation of transcription in prostate cancer cells the expression of was also in cancer cells M. N. M. A. H. M. Cancer Res. 2001; 61: Google Scholar). In we also to demonstrate an effect of PTEN on the by β-catenin of transcription in cells the as to the growth-promoting effect of β-catenin is mediated through of the pathway in prostate cancer other tumor we demonstrate that β-catenin the PI3K/Akt and androgen on results and studies by we our findings in The PI3K/Akt signal phosphorylation and inactivation of GSK3β, in nuclear of β-catenin. β-catenin AR activity to prostate cell growth and survival. the PI3K LY294002 and PTEN negatively regulate inactivation of PTEN has been in which the of and cell progression L.C. Proc. Natl. Acad. Sci. U. S. A. 1999; PubMed Scopus Google Scholar, J. C. S. J. C. S.H. M. H. Science. 1997; PubMed Scopus Google Scholar). the expression of the and the of which results in nuclear β-catenin, also prostate cancer progression Cancer Res. Google Scholar). Our that PTEN reduces nuclear β-catenin in prostate cancer cells suggest a novel role of PTEN in cell growth and survival. further of the of the among PI3K, and the androgen signaling pathways in prostate cancer cells provide fresh into the of prostate cancer that may to pathways that can for prostate cancer Prostate cancer is the most common malignancy in men and the second leading cause of cancer death in the United States (1Landis S.H. Murray T. Bolden S. Wingo P.A. CA-Cancer J. Clin. 1999; 49: 8-31Crossref PubMed Scopus (3127) Google Scholar). The fact that androgen ablation is an effective treatment for the majority of prostate cancers indicates that androgen plays an essential role in regulating the growth of prostate cancer cells (2Kyprianou N. Isaacs J.T. Endocrinology. 1988; 122: 552-562Crossref PubMed Scopus (633) Google Scholar, 3Isaacs J.T. Kyprianou N. Cancer Treat. Res. 1989; 46: 177-193Crossref PubMed Scopus (4) Google Scholar). The growth-promoting effects of androgen in prostate cells are mediated mostly through the androgen receptor (AR).1 The AR belongs to the nuclear receptor superfamily and acts as a ligand-dependent transcription factor (4Chang C.S. Kokontis J. Liao S.T. Science. 1988; 240: 324-326Crossref PubMed Scopus (724) Google Scholar, 5Tsai M.J. O'Malley B.W. Annu. Rev. Biochem. 1994; 63: 451-486Crossref PubMed Scopus (2678) Google Scholar). Recent studies suggest that other signal transduction pathways can modulate AR activity and that they may also contribute to the development and progression of prostate cancer (6Jenster G. Semin. Oncol. 1999; 26: 407-421PubMed Google Scholar, 7Hayes S.A. Zarnegar M. Sharma M. Yang F. Peehl D.M. ten Dijke P. Sun Z. Cancer Res. 2001; 61: 2112-2118PubMed Google Scholar). The phosphatidylinositol 3-kinase (PI3K) consists of regulatory (p85) and catalytic (p110) subunits that participate in multiple cellular processes including cell growth, transformation, differentiation, and survival (8Carpenter C.L. Cantley L.C. Curr. Opin. Cell Biol. 1996; 8: 153-158Crossref PubMed Scopus (575) Google Scholar). An oncoprotein, Akt/PKB, has been identified as a key effector of the PI3K signaling pathway (9Datta S.R. Dudek H. Tao X. Masters S., Fu, H. Gotoh Y. Greenberg M.E. Cell. 1997; 91: 231-241Abstract Full Text Full Text PDF PubMed Scopus (4914) Google Scholar, 10Kauffmann-Zeh A. Rodriguez-Viciana P. Ulrich E. Gilbert C. Coffer P. Downward J. Evan G. Nature. 1997; 385: 544-548Crossref PubMed Scopus (1068) Google Scholar). The binding of PI3K-generated phospholipids to Akt results in the translocation of Akt from the cytoplasm to the inner surface of the plasma membrane where Akt is phosphorylated by the upstream kinases, PDK-1, PDK-2, and ILK (11Andjelkovic M. Jakubowicz T. Cron P. Ming X.F. Han J.W. Hemmings B.A. Proc. Natl. Acad. Sci. U. S. A. 1996; 93: 5699-5704Crossref PubMed Scopus (427) Google Scholar, 12Franke T.F. Kaplan D.R. Cantley L.C. Cell. 1997; 88: 435-437Abstract Full Text Full Text PDF PubMed Scopus (1513) Google Scholar). The activation of Akt results in the phosphorylation of a number of downstream substrates such as glycogen synthase kinase (GSK3), Bad, and caspase9 and the forkhead transcription factors, Raf, Iκb kinase, and phosphodiesterase 3B (13Datta S.R. Brunet A. Greenberg M.E. Genes Dev. 1999; 13: 2905-2927Crossref PubMed Scopus (3707) Google Scholar). As one of the principal physiological substrates of Akt, GSK3 is a ubiquitously expressed protein serine/threonine kinase that was initially identified as an that glycogen in to D.R. P. M. Hemmings B.A. Nature. PubMed Scopus Google Scholar, Biochem. J. 1994; PubMed Scopus Google Scholar). has been shown that plays an role in the pathway by regulating the degradation of β-catenin J. N. Y. Acad. Sci. PubMed Scopus Google Scholar, C. J. Biol. 1997; Full Text Full Text PDF PubMed Scopus Google Scholar). β-catenin plays a role in cell and in the signaling pathway P. Genes Dev. PubMed Google Scholar). to in β-catenin is to cellular of the β-catenin is in the cell membrane where is the of a protein in M. H. J. 1989; 8: PubMed Scopus Google Scholar). of β-catenin is in the and cytoplasm where signaling. In the of a β-catenin is by a GSK3β, and the tumor the phosphorylation of and in the of β-catenin and target for degradation by the pathway H. A. J. A. J. 1997; PubMed Scopus Google Scholar). signaling which to an accumulation of β-catenin in the and the of of the M. M. M. J. S. J. H. Cell. 1996; Full Text Full Text PDF PubMed Scopus Google and other transcription S. Cancer Res. Google X. Sharma M. Sun Z. J. Biol. Full Text Full Text PDF PubMed Scopus Google Scholar). The tumor PTEN is a phosphatase L.C. Proc. Natl. Acad. Sci. U. S. A. 1999; PubMed Scopus Google Scholar). studies that of PTEN is a common in a of including prostate cancer J. C. S. J. C. S.H. M. H. Science. 1997; PubMed Scopus Google Scholar). PTEN was to in prostate prostate and in prostate cancer cell J. C. S. J. C. S.H. M. H. Science. 1997; PubMed Scopus Google Scholar, P.A. S.A. H. T. T. 1997; PubMed Scopus Google Scholar). In the expression of PTEN protein as as Akt activity has been in X. C.L. Proc. Natl. Acad. Sci. U. S. A. PubMed Scopus Google Scholar). has been shown that PTEN cell growth and transcription in prostate cancer cells P. J. Biol. 2001; Full Text Full Text PDF PubMed Scopus Google Scholar). PI3K/Akt has been shown to prostate cancer cell survival and growth PTEN and the PI3K LY294002 negatively regulate P. J. Biol. 2001; Full Text Full Text PDF PubMed Scopus Google Scholar, G. Cancer Res. Google Scholar). mechanisms have been for the molecular by which and PTEN regulate transcription is currently unclear. a β-catenin and AR was identified by and S. Cancer Res. Google Scholar, X. Sharma M. Sun Z. J. Biol. Full Text Full Text PDF PubMed Scopus Google Scholar). β-catenin the ligand-dependent activity of AR in prostate cancer Here, we provide multiple of evidence that the the androgen and PI3K/Akt pathways is mediated through the of the PI3K/Akt downstream effector inactivation by phosphorylation results in nuclear of β-catenin, which AR activity. findings delineate a novel mechanism by which PI3K/Akt and PTEN regulate the androgen pathway prostate cell growth and survival. pathway plays a critical role in prostate cell and survival L.C. Proc. Natl. Acad. Sci. U. S. A. 1999; PubMed Scopus Google Scholar). PTEN, which is in prostate cancer negatively by blocking the PI3K/Akt of evidence that PI3K/Akt and PTEN can modulate cell growth and transcription in prostate cancer cells P. J. Biol. 2001; Full Text Full Text PDF PubMed Scopus Google Scholar, G. Cancer Res. Google a link the PI3K/Akt and androgen In we that β-catenin acts as the of for the the PI3K/Akt and androgen signaling The are is the degradation of β-catenin by GSK3β, a downstream effector of PI3K/Akt, and our recent that β-catenin AR and ligand-dependent transcription X. Sharma M. Sun Z. J. Biol. Full Text Full Text PDF PubMed Scopus Google Scholar).The of β-catenin expression and signaling is as in the of of including prostate cancer P. Genes Dev. PubMed Google Scholar, Cancer Res. Google Scholar). cells of cellular β-catenin by in the of the by regulatory in β-catenin other signaling pathways are also in regulating cellular β-catenin Proc. Natl. Acad. Sci. U. S. A. PubMed Scopus Google Scholar, C. A. M.J. F. G. C. J. 2001; PubMed Scopus Google Scholar, D.M. J. 2001; PubMed Scopus Google Scholar). In we that PI3K/Akt the of nuclear β-catenin by phosphorylation and inactivation of the downstream substrate in prostate cancer Given that β-catenin acts as a coactivator of AR, provide evidence to suggest a mechanism whereby PI3K/Akt can prostate cell and survival through androgen studies that PTEN negatively the PI3K/Akt pathway in prostate cancer cells P. J. Biol. 2001; Full Text Full Text PDF PubMed Scopus Google Scholar). The expression of PTEN in a PTEN-null prostate cancer cell line, cell growth and In we that the of PTEN in reduces β-catenin-mediated augmentation of AR PTEN effect in cells β-catenin mutants a the phosphorylation The results from our further that PTEN reduces the nuclear accumulation of β-catenin in prostate the β-catenin mutants in our are to degradation by the we that the of β-catenin by PTEN is mediated through Our results are a recent that nuclear β-catenin protein is in PTEN and expression can the of PTEN S. S. J. Cell Biol. 2001; PubMed Scopus Google Scholar). The also that PTEN negatively the PI3K pathway by phosphorylation of In the PTEN as a PI3K are our the effects mediated by the PI3K of the AR protein such as by phosphorylation has been to an mechanism for AR activity in prostate cancer cells M. C. J. J. Biol. Full Text Full Text PDF PubMed Scopus Google Scholar, Res. 1996; PubMed Scopus Google Scholar, T. N. J. Biol. Full Text Full Text PDF PubMed Scopus Google Scholar). The for Akt phosphorylation identified in the and the binding of AR G. Cancer Res. Google Scholar). that Akt can to and AR G. Cancer Res. Google Scholar). However, and we to show a Akt and AR the phosphorylation of AR by Akt in to also by P. J. Biol. 2001; Full Text Full Text PDF PubMed Scopus Google Scholar). results may to the of and they also suggest that other pathways may in As in we a novel molecular mechanism for PI3K/Akt and PTEN of androgen signaling in prostate cancer role of β-catenin in has been the transcription Curr. Opin. Cell Biol. 1999; PubMed Scopus Google Scholar). as we and have X. Sharma M. Sun Z. J. Biol. Full Text Full Text PDF PubMed Scopus Google Scholar, G. 2001; β-catenin is shown to have effect on the activation of transcription in prostate cancer cells the expression of was also in cancer cells M. N. M. A. H. M. Cancer Res. 2001; 61: Google Scholar). In we also to demonstrate an effect of PTEN on the by β-catenin of transcription in cells the as to the growth-promoting effect of β-catenin is mediated through of the pathway in prostate cancer other tumor we demonstrate that β-catenin the PI3K/Akt and androgen on results and studies by we our findings in The PI3K/Akt signal phosphorylation and inactivation of GSK3β, in nuclear of β-catenin. β-catenin AR activity to prostate cell growth and survival. the PI3K LY294002 and PTEN negatively regulate inactivation of PTEN has been in which the of and cell progression L.C. Proc. Natl. Acad. Sci. U. S. A. 1999; PubMed Scopus Google Scholar, J. C. S. J. C. S.H. M. H. Science. 1997; PubMed Scopus Google Scholar). the expression of the and the of which results in nuclear β-catenin, also prostate cancer progression Cancer Res. Google Scholar). Our that PTEN reduces nuclear β-catenin in prostate cancer cells suggest a novel role of PTEN in cell growth and survival. further of the of the among PI3K, and the androgen signaling pathways in prostate cancer cells provide fresh into the of prostate cancer that may to pathways that can for prostate cancer The pathway plays a critical role in prostate cell and survival L.C. Proc. Natl. Acad. Sci. U. S. A. 1999; PubMed Scopus Google Scholar). PTEN, which is in prostate cancer negatively by blocking the PI3K/Akt of evidence that PI3K/Akt and PTEN can modulate cell growth and transcription in prostate cancer cells P. J. Biol. 2001; Full Text Full Text PDF PubMed Scopus Google Scholar, G. Cancer Res. Google a link the PI3K/Akt and androgen In we that β-catenin acts as the of for the the PI3K/Akt and androgen signaling The are is the degradation of β-catenin by GSK3β, a downstream effector of PI3K/Akt, and our recent that β-catenin AR and ligand-dependent transcription X. Sharma M. Sun Z. J. Biol. Full Text Full Text PDF PubMed Scopus Google Scholar). The of β-catenin expression and signaling is as in the of of including prostate cancer P. Genes Dev. PubMed Google Scholar, Cancer Res. Google Scholar). cells of cellular β-catenin by in the of the by regulatory in β-catenin other signaling pathways are also in regulating cellular β-catenin Proc. Natl. Acad. Sci. U. S. A. PubMed Scopus Google Scholar, C. A. M.J. F. G. C. J. 2001; PubMed Scopus Google Scholar, D.M. J. 2001; PubMed Scopus Google Scholar). In we that PI3K/Akt the of nuclear β-catenin by phosphorylation and inactivation of the downstream substrate in prostate cancer Given that β-catenin acts as a coactivator of AR, provide evidence to suggest a mechanism whereby PI3K/Akt can prostate cell and survival through androgen signaling. studies that PTEN negatively the PI3K/Akt pathway in prostate cancer cells P. J. Biol. 2001; Full Text Full Text PDF PubMed Scopus Google Scholar). The expression of PTEN in a PTEN-null prostate cancer cell line, cell growth and In we that the of PTEN in reduces β-catenin-mediated augmentation of AR PTEN effect in cells β-catenin mutants a the phosphorylation The results from our further that PTEN reduces the nuclear accumulation of β-catenin in prostate the β-catenin mutants in our are to degradation by the we that the of β-catenin by PTEN is mediated through Our results are a recent that nuclear β-catenin protein is in PTEN and expression can the of PTEN S. S. J. Cell Biol. 2001; PubMed Scopus Google Scholar). The also that PTEN negatively the PI3K pathway by phosphorylation of In the PTEN as a PI3K are our the effects mediated by the PI3K of the AR protein such as by phosphorylation has been to an mechanism for AR activity in prostate cancer cells M. C. J. J. Biol. Full Text Full Text PDF PubMed Scopus Google Scholar, Res. 1996; PubMed Scopus Google Scholar, T. N. J. Biol. Full Text Full Text PDF PubMed Scopus Google Scholar). The for Akt phosphorylation identified in the and the binding of AR G. Cancer Res. Google Scholar). that Akt can to and AR G. Cancer Res. Google Scholar). However, and we to show a Akt and AR the phosphorylation of AR by Akt in to also by P. J. Biol. 2001; Full Text Full Text PDF PubMed Scopus Google Scholar). results may to the of and they also suggest that other pathways may in As in we a novel molecular mechanism for PI3K/Akt and PTEN of androgen signaling in prostate cancer The role of β-catenin in has been the transcription Curr. Opin. Cell Biol. 1999; PubMed Scopus Google Scholar). as we and have X. Sharma M. Sun Z. J. Biol. Full Text Full Text PDF PubMed Scopus Google Scholar, G. 2001; β-catenin is shown to have effect on the activation of transcription in prostate cancer cells the expression of was also in cancer cells M. N. M. A. H. M. Cancer Res. 2001; 61: Google Scholar). In we also to demonstrate an effect of PTEN on the by β-catenin of transcription in cells the as to the growth-promoting effect of β-catenin is mediated through of the pathway in prostate cancer other tumor In we demonstrate that β-catenin the PI3K/Akt and androgen on results and studies by we our findings in The PI3K/Akt signal phosphorylation and inactivation of GSK3β, in nuclear of β-catenin. β-catenin AR activity to prostate cell growth and survival. the PI3K LY294002 and PTEN negatively regulate inactivation of PTEN has been in which the of and cell progression L.C. Proc. Natl. Acad. Sci. U. S. A. 1999; PubMed Scopus Google Scholar, J. C. S. J. C. S.H. M. H. Science. 1997; PubMed Scopus Google Scholar). the expression of the and the of which results in nuclear β-catenin, also prostate cancer progression Cancer Res. Google Scholar). Our that PTEN reduces nuclear β-catenin in prostate cancer cells suggest a novel role of PTEN in cell growth and survival. further of the of the among PI3K, and the androgen signaling pathways in prostate cancer cells provide fresh into the of prostate cancer that may to pathways that can for prostate cancer are to and for the for and in