期刊
NATURE COMMUNICATIONS
卷 10, 期 -, 页码 -出版社
NATURE PUBLISHING GROUP
DOI: 10.1038/s41467-019-08574-7
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资金
- Hong Kong Research Grants Council [27103616]
- National Natural Science Foundation of China [81703066, 81772777]
- Ovarian Cancer Research Foundation
- NCI [1P50 CA217685-01, 1U01 CA217842-01, CA016672]
- Health and Medical Research Fund
- Hong Kong Special Administrative Region [03143006]
- Shanghai Pujiang Program [17PJ1401400]
Copy number loss of PIK3R1 (p85 alpha) 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 p110 alpha 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.
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