Sun Zicheng, Jiang Qiwei, Gao Bing, Zhang Xiaomei, Bu Lang, Wang Lei, Lin Ying, Xie Wei, Li Jie, Guo Jianping
Department of Breast and Thyroid Surgery, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong, China.
Institute of Precision Medicine, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong, China.
Cancer Res. 2023 Apr 14;83(8):1264-1279. doi: 10.1158/0008-5472.CAN-22-3407.
The PI3K-AKT signaling pathway is frequently dysregulated in cancer, and it is hyperactivated in approximately 50% of breast cancers. Although inhibitors directly targeting the PI3K-AKT axis have been developed, clinical efficacy has been limited to only a subset of patients. Identification of mechanisms underlying AKT-driven tumorigenesis could lead to alternative approaches to block pathway signaling and suppress breast tumor growth. Mass spectrometry-based analyses demonstrated that salt-inducible kinase 1 (SIK1) binds AKT and undergoes AKT-mediated phosphorylation, which compromises SIK1 tumor-suppressive functions. As a result, AKT relieved the binding and repression of STAT3 by SIK1 in a phosphorylation-dependent manner, resulting in breast cell tumorigenesis. Following AKT-mediated phosphorylation, SIK1 interacted with 14-3-3 and was translocated to the cytoplasm where the isomerase Pin1 facilitated SIK1 interaction with the E3 ligase ITCH to promote SIK1 ubiquitination and subsequent degradation. These findings indicate that SIK1 is a substrate of AKT that links AKT oncogenic function to STAT3 activation, highlighting targeting of the JAK2-STAT3 axis as a strategy to treat AKT-driven breast cancer.
AKT binds and phosphorylates SIK1 to overcome SIK1-mediated repression of STAT3, indicating that STAT3 is a potential therapeutic target in breast cancer with hyperactive AKT signaling.
PI3K-AKT信号通路在癌症中经常失调，在大约50%的乳腺癌中过度激活。尽管已经开发出直接靶向PI3K-AKT轴的抑制剂，但其临床疗效仅限于一部分患者。确定AKT驱动肿瘤发生的潜在机制可能会带来阻断通路信号和抑制乳腺肿瘤生长的替代方法。基于质谱的分析表明，盐诱导激酶1（SIK1）与AKT结合并经历AKT介导的磷酸化，这损害了SIK1的肿瘤抑制功能。结果，AKT以磷酸化依赖的方式解除了SIK1对STAT3的结合和抑制，导致乳腺细胞肿瘤发生。在AKT介导的磷酸化之后，SIK1与14-3-3相互作用并转运到细胞质中，在那里异构酶Pin1促进了SIK1与E3连接酶ITCH的相互作用，以促进SIK1的泛素化和随后的降解。这些发现表明，SIK1是AKT的底物，它将AKT的致癌功能与STAT3激活联系起来，突出了靶向JAK2-STAT3轴作为治疗AKT驱动的乳腺癌的一种策略。
AKT结合并磷酸化SIK1以克服SIK1介导的对STAT3的抑制，表明STAT3是AKT信号过度活跃的乳腺癌中的一个潜在治疗靶点。
