Abstract
Copy number loss of PIK3R1 (p85α) most commonly occurs in ovarian cancer among all cancer types. Here we report that ovarian cancer cells manifest a spectrum of tumorigenic phenotypes upon knockdown of PIK3R1. PIK3R1 loss activates AKT and p110-independent JAK2/STAT3 signaling through inducing changes in the phosphorylation of the docking protein Gab2, thereby relieving the negative inhibition on AKT and promoting the assembly of JAK2/STAT3 signalosome, respectively. Additional mechanisms leading to AKT activation include enhanced p110α kinase activity and a decrease in PTEN level. PIK3R1 loss renders ovarian cancer cells vulnerable to inhibition of AKT or JAK2/STAT3. The combination of AKT and STAT3 inhibitors significantly increases the anti-tumor effect compared to single-agent treatments. Together, our findings provide a rationale for mechanism-based therapeutic approach that targets tumors with loss of PIK3R1.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Adaptor Proteins, Signal Transducing / metabolism*
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Apoptosis / physiology
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Cell Cycle / physiology
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Cell Movement / physiology
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Cell Proliferation / physiology
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Cell Survival / physiology
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Class I Phosphatidylinositol 3-Kinases / metabolism
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Class Ia Phosphatidylinositol 3-Kinase
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Female
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Humans
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Janus Kinase 2 / metabolism
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Ovarian Neoplasms / enzymology
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Ovarian Neoplasms / metabolism*
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Ovarian Neoplasms / pathology
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PTEN Phosphohydrolase / metabolism
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Phosphatidylinositol 3-Kinases / deficiency
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Phosphatidylinositol 3-Kinases / metabolism*
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Phosphorylation
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Proto-Oncogene Proteins c-akt / metabolism*
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STAT3 Transcription Factor / metabolism*
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Signal Transduction
Substances
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Adaptor Proteins, Signal Transducing
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GAB2 protein, human
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STAT3 Transcription Factor
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STAT3 protein, human
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PIK3R1 protein, human
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Class I Phosphatidylinositol 3-Kinases
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Class Ia Phosphatidylinositol 3-Kinase
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PIK3CA protein, human
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JAK2 protein, human
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Janus Kinase 2
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Proto-Oncogene Proteins c-akt
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PTEN Phosphohydrolase
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PTEN protein, human