title: Casein kinase 1α-dependent feedback loop controls autophagy in RAS-driven cancers.
abstract: 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 1α (CK1α), a ubiquitously expressed serine/threonine kinase, is a key negative regulator of oncogenic RAS-induced autophagy. Depletion or pharmacologic inhibition of CK1α 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 CK1α, as depletion of CK1α reduced levels of phosphorylated FOXO3A and increased expression of FOXO3A-responsive genes. Oncogenic RAS increased CK1α protein abundance via activation of the PI3K/AKT/mTOR pathway. In turn, elevated levels of CK1α 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 CK1α 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 CK1α-regulated autophagy offers a potential therapeutic opportunity to treat oncogenic RAS-driven cancers.
authors: Jit Kong
authors: JK
authors: Cheong
authors: Fuquan
authors: F
authors: Zhang
authors: Pei Jou
authors: PJ
authors: Chua
authors: Boon Huat
authors: BH
authors: Bay
authors: Andrew
authors: A
authors: Thorburn
authors: David M
authors: DM
authors: Virshup
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D001343:Autophagy / Q000502:physiology*; D047389:Casein Kinase I / Q000037:antagonists & inhibitors / Q000502:physiology*; D025461:Feedback, Physiological; D005347:Fibroblasts / Q000201:enzymology / Q000502:physiology; D000071316:Forkhead Box Protein O3; D051858:Forkhead Transcription Factors / Q000378:metabolism; D015972:Gene Expression Regulation, Neoplastic / Q000235:genetics; D006801:Humans; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D008969:Molecular Sequence Data; D009363:Neoplasm Proteins / Q000502:physiology*; D009368:Neoplasm Transplantation; D009369:Neoplasms / Q000201:enzymology*; D015689:Oncogene Protein p21(ras) / Q000502:physiology*; D019869:Phosphatidylinositol 3-Kinases / Q000502:physiology; D010766:Phosphorylation; D011499:Protein Processing, Post-Translational; D051057:Proto-Oncogene Proteins c-akt / Q000502:physiology; D034741:RNA, Small Interfering / Q000494:pharmacology; D016415:Sequence Alignment; D017386:Sequence Homology, Amino Acid; D058570:TOR Serine-Threonine Kinases / Q000502:physiology; D015533:Transcriptional Activation
chemical_list: D047389:Casein Kinase I; D000071316:Forkhead Box Protein O3; D051858:Forkhead Transcription Factors; D009363:Neoplasm Proteins; D015689:Oncogene Protein p21(ras); D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt; D034741:RNA, Small Interfering; D058570:TOR Serine-Threonine Kinases; C499517:FOXO3 protein, human; C546842:MTOR protein, human; C494918:AKT1 protein, human