期刊
JOURNAL OF CLINICAL INVESTIGATION
卷 125, 期 4, 页码 1401-1418出版社
AMER SOC CLINICAL INVESTIGATION INC
DOI: 10.1172/JCI78018
关键词
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资金
- Duke-NUS Signature Research Program - Agency for Science, Technology and Research, Singapore
- Ministry of Health, Singapore
- Singapore Translational Research Investigator Award - National Research Foundation
- National Medical Research Council (NMRC) [NMRC/STaR/R-913-301-006-213]
- NMRC-Cooperative Basic Research Grant (NMRC-CBRG) [NMRC/BNIG/1078/2012]
Activating mutations in the RAS oncogene are common in cancer but are difficult to therapeutically target. RAS activation promotes autophagy, a highly regulated catabolic process that metabolically buffers cells in response to diverse stresses. Here we report that casein kinase 1 alpha (CK1 alpha), a ubiquitously expressed serine/threonine kinase, is a key negative regulator of oncogenic RAS-induced autophagy. Depletion or pharmacologic inhibition of CK1 alpha enhanced autophagic flux in oncogenic RAS-driven human fibroblasts and multiple cancer cell lines. FOXO3A, a master longevity mediator that transcriptionally regulates diverse autophagy genes, was a critical target of CK1 alpha, as depletion of CK1 alpha reduced levels of phosphorylated FOXO3A and increased expression of FOXO3A-responsive genes. Oncogenic RAS increased CK1 alpha protein abundance via activation of the PI3K/AKT/mTOR pathway. In turn, elevated levels of CK1 alpha increased phosphorylation of nuclear FOXO3A, thereby inhibiting transactivation of genes critical for RAS-induced autophagy. In both RAS-driven cancer cells and murine xenograft models, pharmacologic CK1 alpha inactivation synergized with lysosomotropic agents to inhibit growth and promote tumor cell death. Together, our results identify a kinase feedback loop that influences RAS-dependent autophagy and suggest that targeting CK1 alpha-regulated autophagy offers a potential therapeutic opportunity to treat oncogenic RAS-driven cancers.
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