School of Biomedical Sciences, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong, Hong Kong.
Knight Cancer Institute, Oregon Health and Science University, Portland, Oregon, USA.
Nat Commun. 2020 May 8;11(1):2291. doi: 10.1038/s41467-020-16061-7.
PIK3R2 encodes the p85β regulatory subunit of phosphatidylinositol 3-kinase and is frequently amplified in cancers. The signaling mechanism and therapeutic implication of p85β are poorly understood. Here we report that p85β upregulates the protein level of the receptor tyrosine kinase AXL to induce oncogenic signaling in ovarian cancer. p85β activates p110 activity and AKT-independent PDK1/SGK3 signaling to promote tumorigenic phenotypes, which are all abolished upon inhibition of AXL. At the molecular level, p85β alters the phosphorylation of TRIM2 (an E3 ligase) and optineurin (an autophagy receptor), which mediate the selective regulation of AXL by p85β, thereby disrupting the autophagic degradation of the AXL protein. Therapeutically, p85β expression renders ovarian cancer cells vulnerable to inhibitors of AXL, p110, or PDK1. Conversely, p85β-depleted cells are less sensitive to these inhibitors. Together, our findings provide a rationale for pharmacological blockade of the AXL signaling axis in PIK3R2-amplified ovarian cancer.
PIK3R2 编码磷脂酰肌醇 3-激酶的 p85β 调节亚基，并且在癌症中经常被扩增。p85β 的信号转导机制和治疗意义还知之甚少。在这里，我们报告 p85β 上调受体酪氨酸激酶 AXL 的蛋白水平，从而在卵巢癌中诱导致癌信号。p85β 激活 p110 活性和 AKT 非依赖性 PDK1/SGK3 信号通路，促进致瘤表型，而这些表型在抑制 AXL 后均被消除。在分子水平上，p85β 改变了 TRIM2（一种 E3 连接酶）和 optineurin（一种自噬受体）的磷酸化，这介导了 p85β 对 AXL 的选择性调节，从而破坏了 AXL 蛋白的自噬降解。在治疗上，p85β 的表达使卵巢癌细胞对 AXL、p110 或 PDK1 的抑制剂敏感。相反，p85β 耗尽的细胞对这些抑制剂的敏感性降低。总之，我们的研究结果为在 PIK3R2 扩增的卵巢癌中阻断 AXL 信号轴提供了药理学依据。
