Department of Microbiology, Sun Yat-sen University Zhongshan School of Medicine, Guangzhou, China.
Guangdong Key Laboratory of Liver Disease Research, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, China.
Nat Cell Biol. 2018 Apr;20(4):465-478. doi: 10.1038/s41556-018-0065-8. Epub 2018 Mar 28.
The contribution of autophagy to cancer development remains controversial, largely owing to the fact that autophagy can be tumour suppressive or oncogenic in different biological contexts. Here, we show that in non-small-cell lung cancer (NSCLC), casein kinase 1 alpha 1 (CK1α) suppresses tumour growth by functioning as an autophagy inducer to activate an autophagy-regulating, tumour-suppressive PTEN/AKT/FOXO3a/Atg7 axis. Specifically, CK1α bound the C-terminal tail of PTEN and enhanced both PTEN stability and activity by competitively antagonizing NEDD4-1-induced PTEN polyubiquitination and abrogating PTEN phosphorylation, thereby inhibiting AKT activity and activating FOXO3a-induced transcription of Atg7. Notably, blocking CK1α-induced Atg7-dependent autophagy cooperates with oncogenic HRas to initiate tumorigenesis of lung epithelial cells. An association of a CK1α-modulated autophagic program with the anti-neoplastic activities of the CK1α/PTEN/FOXO3a/Atg7 axis was demonstrated in xenografted tumour models and human NSCLC specimens. This provides insights into the biological and potentially clinical significance of autophagy in NSCLC.
自噬在癌症发展中的作用仍然存在争议，主要是因为自噬在不同的生物学环境中可能具有抑癌或致癌作用。在这里，我们表明在非小细胞肺癌（NSCLC）中，酪蛋白激酶 1α（CK1α）通过作为自噬诱导物发挥作用，激活自噬调节、肿瘤抑制的 PTEN/AKT/FOXO3a/Atg7 轴，从而抑制肿瘤生长。具体而言，CK1α 结合 PTEN 的 C 端尾巴，并通过竞争性拮抗 NEDD4-1 诱导的 PTEN 多泛素化和消除 PTEN 磷酸化，增强 PTEN 的稳定性和活性，从而抑制 AKT 活性并激活 FOXO3a 诱导的 Atg7 转录。值得注意的是，阻断 CK1α 诱导的 Atg7 依赖性自噬与致癌性 HRas 一起协同作用，引发肺上皮细胞的肿瘤发生。在异种移植肿瘤模型和人 NSCLC 标本中证实了 CK1α 调节的自噬程序与 CK1α/PTEN/FOXO3a/Atg7 轴的抗肿瘤活性之间的关联。这为自噬在 NSCLC 中的生物学和潜在临床意义提供了新的见解。
