Cited by 92Prostate Cancer Treatment and ResearchPI3K/AKT/mTOR signaling in cancerLipid Membrane Structure and Behavior

Phosphoinositide 3-Kinase-independent Non-genomic Signals Transit from the Androgen Receptor to Akt1 in Membrane Raft Microdomains

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Cinar, Bekir, Mukhopadhyay, Nishit K., Meng, Gaoyuan, Freeman, Michael R.·2007·Journal of Biological Chemistry

Abstract

The serine-threonine kinase, Akt1/protein kinase Balpha is an important mediator of growth, survival, and metabolic signaling. Recent studies have implicated cholesterol-rich, lipid raft microdomains in survival signals mediated by Akt1. Here we address the role of lipid raft membranes as a potential site of intersection of androgenic and Akt1 signaling. A subpopulation of androgen receptor (AR) was found to localize to a lipid raft subcellular compartment in LNCaP prostate cancer cells. Endogenous AR interacted with endogenous Akt1 preferentially in lipid raft fractions and androgen substantially enhanced the interaction between the two proteins. The association of AR with Akt1 was inhibited by the anti-androgen, bicalutamide, but was not affected by inhibition of phosphoinositide 3-kinase (PI3K). Androgen promoted endogenous Akt1 activity in lipid raft fractions, in a PI3K-independent manner, within 10 min of treatment. Fusion of a lipid raft targeting sequence to AR enhanced localization of the receptor to rafts, and stimulated Akt1 activity in response to androgen, while reducing the cells' dependence on constitutive signaling through PI3K for cell survival. These findings suggest that signals channeled through AR and Akt1 intersect by a mechanism involving formation within lipid raft membranes of an androgen-responsive, extranuclear AR/Akt1 complex. Our results indicate that cholesterol-rich membrane microdomains play a role in transmitting non-genomic signals involving androgen and the Akt pathway in prostate cancer cells.

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Crossref · 10.1074/jbc.m703310200

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  • Testosterone has been shown to induce its effects through binding to intracellular androgen receptors (ARs), which then regulate gene transcription.

    “Testosterone has been shown to induce its effects through binding to intracellular androgen receptors (ARs) (34), which then regulate gene transcription (18, 81).”

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Authors
Cinar, B., Mukhopadhyay, N. K., Meng, G., & Freeman, M. R.
Affiliations
Boston Children's Hospital (US)
Corresponding author
Freeman, Michael R.
Venue
Journal of Biological Chemistry
Publisher
Elsevier BV
Published
2007-10
Volume
282
Issue
40
Pages
29584-29593
ISSN
0021-9258 (ISSN-L)
OpenAlex
W2028828998
Cited by
92
References
48
Citations by year
2025: 3 · 2024: 3 · 2022: 1 · 2021: 4 · 2020: 4 · 2019: 4 · 2018: 2 · 2017: 5 · 2016: 3 · 2015: 3 · 2014: 3 · 2013: 10 · 2012: 12
FWCI
6.62
Type
journal article
Language
en
Open access
Locations
  • Journal of Biological Chemistry (publishedVersion, cc-by)
  • PubMed (publishedVersion)
Funders
  • National Institutes of Health (5r01ca112303-05)
  • National Cancer Institute (R01-CA-112303)
  • National Institute of Diabetes and Digestive and Kidney Diseases (R37 DK47556, R01DK087806, P50DK65298, R37DK047556, P50DK065298)
Topics
  • Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Prostate Cancer Treatment and Research
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › PI3K/AKT/mTOR signaling in cancer
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Lipid Membrane Structure and Behavior
Keywords
androgen receptor, AKT1, lipid rafts, non-genomic signaling, cholesterol, prostate cancer, LNCaP cells, bicalutamide, phosphatidylinositol 3-kinase, cell survival signaling, receptor-protein interactions
MeSH terms
Animals, Cell Survival, Chlorocebus aethiops, Humans, Male, Plasmids, Prostatic Neoplasms, Receptors, Androgen, Signal Transduction, Gene Expression Regulation, Enzymologic, COS Cells, Phosphatidylinositol 3-Kinases, Membrane Microdomains, Cell Line, Tumor, Proto-Oncogene Proteins c-akt

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