Deregulated Gab2 phosphorylation mediates aberrant AKT and STAT3 signaling upon PIK3R1 loss in ovarian cancer
Year: 2019
Type: article
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.
Source: Nature Communications
Language: English
Subfield: Molecular Biology
Domain: Life Sciences
Open Access status: gold
Estimated APC paid: $5,200
Funders: Dr. Miriam and Sheldon G. Adelson Medical Research Foundation, Ovarian Cancer Research Foundation, National Natural Science Foundation of China, University of Texas MD Anderson Cancer Center, University of California, San Diego, Health and Medical Research Fund, RIKEN, National Cancer Institute
Awards: Functional Proteomics by Reverse Phase Protein Array in Cancer, U.T. M. D. Anderson Cancer Center SPORE in Ovarian Cancer, G1468253849, p21 activated kinase 4 and ovarian cancer chemoresistance, G2905010575, G40523054, G5009597576, Integrative bioinformatics and functional characterization of oncogenic driver aberrations in cancer, Cancer Center Support Grant
OpenAlex ID: W2911788560