Kim Hyun-Jung, Lee Soo Yoon, Kim Chan Young, Kim Yun Hwan, Ju Woong, Kim Seung Cheol
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.
Oncotarget. 2017 Jan 24;8(4):6608-6622. doi: 10.18632/oncotarget.14245.
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.
自噬是一种由溶酶体介导的降解和循环过程，在抗癌治疗期间作为一种适应性生存机制发挥作用。磷酸肌醇-3-激酶（PI3K）通路的异常激活经常发生在包括宫颈癌在内的实体瘤中。然而，单药PI3K抑制剂在临床上显示出适度的抗肿瘤疗效。为了探究自噬抑制是否能提高PI3K抑制剂对PIK3CA突变癌细胞的疗效，研究人员用泛PI3K抑制剂BKM120和自噬抑制剂羟氯喹（HCQ）处理细胞。自噬抑制增强了BKM120的疗效，这取决于PIK3CA突变癌细胞的类型。BKM120处理导致Caski和T47D细胞中叉头框O3（FOXO3a）的核积累，这显示了BKM120和HCQ的协同作用以及自噬的强烈诱导。然而，在C33A和ME180细胞中，大多数FOXO3a仍留在细胞质中，并未表现出协同作用。这些数据表明，BKM120诱导的FOXO3a核转位可能引发自噬，并且是决定BKM120和HCQ在PIK3CA突变癌细胞中协同活性的关键因素。BV02或14-3-3基因敲低使FOXO3a从14-3-3中释放，从而在C33A细胞中通过BKM120诱导自噬，并使细胞对BKM120和HCQ联合治疗敏感，这表明即使在存在BKM120的情况下，14-3-3对FOXO3a的细胞质滞留也会抑制自噬诱导以及BKM120和HCQ联合的协同效应。综上所述，我们的研究表明，FOXO3a的亚细胞定位可能是预测PIK3CA突变宫颈癌患者对PI3K和自噬抑制剂联合治疗反应的潜在生物标志物。
