The DOI matches its Crossref record; 7 of the 7 references it cites were found in a registry or an index.
Phosphatidylinositol 3-Kinase/Akt Stimulates Androgen Pathway through GSK3β Inhibition and Nuclear β-Catenin Accumulation
Open accessAbstract
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 GSK3beta, a downstream substrate of PI3K/Akt, which results in the nuclear accumulation of beta-catenin. Given the recent evidence that beta-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 beta-catenin-mediated augmentation of AR transactivation. Using the mutants of beta-catenin, we further demonstrate that the repressive effect of PTEN is mediated by a GSK3beta-regulated degradation of beta-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.
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Cites
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Linking β-Catenin to Androgen-signaling Pathway
Yang, F., Li, X., Sharma, M., Sasaki, C. Y., Longo, D. L., Lim, B., & Sun, Z. (2002) · Journal of Biological Chemistry · doi:10.1074/jbc.m111962200 · Cited by 342
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Cited by
Ellison, D. W., Onilude, O. E., Lindsey, J. C., Lusher, M. E., Weston, C. L., Taylor, R. E., Pearson, A. D., & Clifford, S. C. (2005) · Journal of Clinical Oncology · doi:10.1200/jco.2005.01.5479 · Cited by 435
PTEN-deficient intestinal stem cells initiate intestinal polyposis
He, X. C., Yin, T., Grindley, J. C., Tian, Q., Sato, T., Tao, W. A., Dirisina, R., Porter-Westpfahl, K. S., Hembree, M., Johnson, T., et al. (2007) · Nature Genetics · doi:10.1038/ng1928 · Cited by 417
Interaction of Nuclear Receptors with the Wnt/β-Catenin/Tcf Signaling Axis: Wnt You Like to Know?
Mulholland, D. J., Dedhar, S., Coetzee, G. A., & Nelson, C. C. (2005) · Endocrine Reviews · doi:10.1210/er.2003-0034 · Cited by 377
Convergence between Wnt-β-catenin and EGFR signaling in cancer
Hu, T., & Li, C. (2010) · Molecular Cancer · doi:10.1186/1476-4598-9-236 · Cited by 291
Wnt/β-catenin signalling in prostate cancer
Kypta, R. M., & Waxman, J. (2012) · Nature Reviews Urology · doi:10.1038/nrurol.2012.116 · Cited by 275
Metadata
- Authors
- Sharma, M., Chuang, W. W., & Sun, Z.
- Venue
- Journal of Biological Chemistry
- Publisher
- Elsevier BV
- Published
- 2002-08
- Volume
- 277
- Issue
- 34
- Pages
- 30935-30941
- ISSN
- 0021-9258 (ISSN-L)
- OpenAlex
- W1980627480
- Cited by
- 308
- References
- 7
- FWCI
- 6.37
- Type
- journal article
- Language
- en
- Open access
- hybrid
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- Sharma, M., Chuang, W. W., & Sun, Z. (2002). Phosphatidylinositol 3-Kinase/Akt Stimulates Androgen Pathway through GSK3β Inhibition and Nuclear β-Catenin Accumulation. Journal of Biological Chemistry. https://doi.org/10.1074/jbc.m201919200
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