title: Subcellular localization of FOXO3a as a potential biomarker of response to combined treatment with inhibitors of PI3K and autophagy in PIK3CA-mutant cancer cells.
abstract: Autophagy is the process of lysosome-mediated degradation and recycling that functions as an adaptive survival mechanism during anti-cancer therapy. Aberrant activation of the phosphoinositide-3-kinase (PI3K) pathway frequently occurs in solid tumors, including cervical cancer. However, single-agent PI3K inhibitors show modest anti-tumor efficacy in clinics. To see whether autophagy inhibition improves the efficacy of PI3K inhibitor in PIK3CA-mutant cancer cells, cells were treated with BKM120, a pan-PI3K inhibitor, and the autophagy inhibitor hydroxychloroquine (HCQ). Autophagy inhibition augmented the efficacy of BKM120 depending on PIK3CA-mutant cancer cell type. BKM120 treatment led to the nuclear accumulation of forkhead box O3 (FOXO3a) in Caski and T47D cells, which showed a synergistic effect of BKM120 and HCQ and the strong induction of autophagy. However, most FOXO3a remained in cytoplasm in C33A and ME180 cells, which did not exhibit synergy. These data suggest that BKM120-induced nuclear translocation of FOXO3a might elicit autophagy and be a critical factor determining the synergistic activity of BKM120 and HCQ in PIK3CA-mutant cancer cells. The release of FOXO3a from 14-3-3 by BV02 or 14-3-3 knockdown induced autophagy by BKM120 in C33A cells and sensitized the cells to the combined BKM120 and HCQ treatment, suggesting that cytoplasmic retention of FOXO3a by 14-3-3 even in the presence of BKM120 inhibit autophagy induction and synergistic effect of BKM120 and HCQ combination. Taken together, our study shows that subcellular localization of FOXO3a might be a potential biomarker for predicting response to the combination treatment with PI3K and autophagy inhibitors in PIK3CA-mutant cervical cancer patients.
authors.affiliation: Innovative Research Center for Control and Prevention of Women's Cancer, Ewha Womans University Mokdong Hospital, Seoul, Korea.|Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, Ewha Womans University Mokdong Hospital, School of Medicine, Ewha Womans University, Seoul, Korea.
authors.forename: Hyun-Jung
authors.initials: HJ
authors.lastname: Kim
authors.affiliation: Department of Obstetrics and Gynecology, Hanmaeum Changwon Hospital, Changwon, Kyungnam, Korea.|Department of Obstetrics and Gynecology, The Graduate School, School of Medicine, Ewha Womans University, Seoul, Korea.
authors.forename: Soo Yoon
authors.initials: SY
authors.lastname: Lee
authors.affiliation: Innovative Research Center for Control and Prevention of Women's Cancer, Ewha Womans University Mokdong Hospital, Seoul, Korea.|Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, Ewha Womans University Mokdong Hospital, School of Medicine, Ewha Womans University, Seoul, Korea.
authors.forename: Chan Young
authors.initials: CY
authors.lastname: Kim
authors.affiliation: Innovative Research Center for Control and Prevention of Women's Cancer, Ewha Womans University Mokdong Hospital, Seoul, Korea.|Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, Ewha Womans University Mokdong Hospital, School of Medicine, Ewha Womans University, Seoul, Korea.
authors.forename: Yun Hwan
authors.initials: YH
authors.lastname: Kim
authors.affiliation: Innovative Research Center for Control and Prevention of Women's Cancer, Ewha Womans University Mokdong Hospital, Seoul, Korea.|Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, Ewha Womans University Mokdong Hospital, School of Medicine, Ewha Womans University, Seoul, Korea.
authors.forename: Woong
authors.initials: W
authors.lastname: Ju
authors.affiliation: Innovative Research Center for Control and Prevention of Women's Cancer, Ewha Womans University Mokdong Hospital, Seoul, Korea.|Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, Ewha Womans University Mokdong Hospital, School of Medicine, Ewha Womans University, Seoul, Korea.
authors.forename: Seung Cheol
authors.initials: SC
authors.lastname: Kim
mesh_terms: D048948:14-3-3 Proteins / Q000235:genetics / Q000378:metabolism; D021581:Active Transport, Cell Nucleus; D000631:Aminopyridines / Q000494:pharmacology*; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology*; D001343:Autophagy / Q000187:drug effects*; D014408:Biomarkers, Tumor / Q000235:genetics / Q000378:metabolism*; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000201:enzymology / Q000235:genetics / Q000473:pathology; D058534:Class I Phosphatidylinositol 3-Kinases / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D003593:Cytoplasm / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D005260:Female; D000071316:Forkhead Box Protein O3 / Q000235:genetics / Q000378:metabolism*; D015972:Gene Expression Regulation, Neoplastic; D006367:HeLa Cells; D006801:Humans; D006886:Hydroxychloroquine / Q000494:pharmacology*; D009025:Morpholines / Q000494:pharmacology*; D009154:Mutation; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D034622:RNA Interference; D015398:Signal Transduction / Q000187:drug effects; D013997:Time Factors; D014162:Transfection; D002583:Uterine Cervical Neoplasms / Q000188:drug therapy* / Q000201:enzymology / Q000235:genetics / Q000473:pathology
chemical_list: D048948:14-3-3 Proteins; D000631:Aminopyridines; D014408:Biomarkers, Tumor; C499517:FOXO3 protein, human; D000071316:Forkhead Box Protein O3; D009025:Morpholines; C571178:NVP-BKM120; D047428:Protein Kinase Inhibitors; C572235:YWHAZ protein, human; D006886:Hydroxychloroquine; D058534:Class I Phosphatidylinositol 3-Kinases; C484760:PIK3CA protein, human
keywords: 14-3-3; FOXO3A; PI3K inhibitor; PIK3CA mutant cervical cancer; autophagy inhibitor