期刊
CANCER CELL
卷 16, 期 1, 页码 21-32出版社
CELL PRESS
DOI: 10.1016/j.ccr.2009.04.012
关键词
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资金
- Prostate Cancer Foundation
- Burroughs-Wellcome Fund
- Department of Defense [PC073284]
- American Society for Clinical Oncology
- Human Frontier Fellowship Organization
- National Human Genome Research Institute
- Susan Madden Fund
- Starr Cancer Consortium [1A-1 1]
- National Institutes of Health [T32CA09172-33, P50CA093459, R33CA128625, P01CA050661, P50CA112967, P30CA14051, R01CA085912, DP20DO02750-01]
- Novartis, Inc
Dysregulation of the phosphatidylinositol 3-kinase (PI3K) signaling pathway occurs frequently in human cancer. PTEN tumor suppressor or PIK3CA oncogene mutations both direct PI3K-dependent tumorigenesis largely through activation of the AKT/PKB kinase. However, here we show through phosphoprotein profiling and functional genomic studies that many PIK3CA mutant cancer cell lines and human breast tumors exhibit only minimal AKT activation and a diminished reliance on AKT for anchorage-independent growth. Instead, these cells retain robust PDK1 activation and membrane localization and exhibit dependency on the PDK1 substrate SGK3. SGK3 undergoes PI3K- and PDK1-dependent activation in PIK3CA mutant cancer cells. Thus, PI3K may promote cancer through both AKT-dependent and AKT-independent mechanisms. Knowledge of differential PI3K/PDK1 signaling could inform rational therapeutics in cancers harboring PIK3CA mutations.
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