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Induction of Androgen Receptor Expression by Phosphatidylinositol 3-Kinase/Akt Downstream Substrate, FOXO3a, and Their Roles in Apoptosis of LNCaP Prostate Cancer Cells
Open accessAbstract
The phosphatidylinositol 3-kinase (PI3K)/Akt pathway plays important roles for prostate cancer cell survival, and the androgen receptor (AR) plays essential roles for prostate cancer cell proliferation. How these two signals cooperate to control cell growth and death, however, remains unclear and debated. Here we provide the first linkage by the identification of Forkhead transcription factor FOXO3a, the PI3K/Akt downstream substrate, as a positive regulator for the induction of AR gene expression. Both Western blot and real time PCR assays demonstrate that FOXO3a can induce AR expression at the protein and mRNA levels, and gel shift and chromatin immunoprecipitation assays further demonstrate that FOXO3a can induce 5' AR promoter activity via binding to the consensus DNA-binding sequence in the AR 5' promoter -1290 to -1297 (5'-TTGTTTCA-3'). Under normal growth conditions, blocking PI3K/Akt signals by LY294002 causes LNCaP cell arrest in G1 phase rather than apoptosis. However, further blocking of AR functions by AR small interfering RNA leads to dramatic LNCaP cell death, suggesting that AR may play important protective roles when the PI3K/Akt signal pathway is blocked by LY294002. Together, our data provide the first model to explain how PI3K/Akt and AR can cooperate to control LNCaP cell growth and death under normal conditions.
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“Moreover, both FOXO3a and GSK-3β modulate transcription of androgen receptor (AR); while the former promotes transcriptional activity of AR (49), the latter acts as its inhibitor (50).”
From Anabolic effect of plant brassinosteroid (2011) · cites this paper as [49]
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Metadata
- Authors
- Yang, L., Xie, S., Jamaluddin, M. S., Altuwaijri, S., Ni, J., Kim, E., Chen, Y.-T., Hu, Y.-C., Wang, L., Chuang, K.-H., Wu, C.-T., & Chang, C.
- Affiliations
- The University of Texas MD Anderson Cancer Center (US)
- University of Rochester Medicine (US)
- Baylor College of Medicine (US)
- Chang Gung University (TW)
- Corresponding author
- Chang, Chawnshang
- ORCID
- Venue
- Journal of Biological Chemistry
- Publisher
- Elsevier BV
- Published
- 2005-09
- Volume
- 280
- Issue
- 39
- Pages
- 33558-33565
- ISSN
- 0021-9258 (ISSN-L)
- OpenAlex
- W2158889317
- Cited by
- 131
- References
- 42
- Citations by year
- 2025: 1 · 2024: 5 · 2023: 5 · 2022: 3 · 2021: 3 · 2020: 4 · 2019: 5 · 2018: 6 · 2017: 5 · 2016: 4 · 2015: 9 · 2014: 6 · 2013: 5 · 2012: 8
- FWCI
- 3.64
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Journal of Biological Chemistry (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Funders
- National Institutes of Health (5r29ca071870-05)
- National Cancer Institute (CA55639, CA-71870)
- National Institute of Diabetes and Digestive and Kidney Diseases (DK 60948, R01DK067686, DK67686, R01DK060948)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › FOXO transcription factor regulation
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Prostate Cancer Treatment and Research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › PI3K/AKT/mTOR signaling in cancer
- Keywords
- androgen receptor, FOXO3, PI3K/Akt signaling, prostate cancer, apoptosis, LNCaP cells, transcriptional regulation, G1 cell cycle arrest, LY294002
- MeSH terms
- Forkhead Box Protein O3, Phosphoinositide-3 Kinase Inhibitors, Chromones, Enzyme Inhibitors, Humans, Male, Models, Biological, Morpholines, Promoter Regions, Genetic, Prostatic Neoplasms, Receptors, Androgen, RNA, Messenger, Gene Expression Regulation, Neoplastic, Apoptosis, Prostate-Specific Antigen, Phosphatidylinositol 3-Kinases, RNA, Small Interfering, Cell Line, Tumor, Chromatin Immunoprecipitation, Forkhead Transcription Factors, Androgen Receptor Antagonists
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