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 Cheong, Fuquan Zhang, Pei Jou Chua, Boon Huat Bay, Andrew Thorburn, David M Virshup
• Journal: The Journal of clinical investigation (J Clin Invest) Vol. 125 Issue 4 Pg. 1401-18 (Apr 2015) ISSN: 1558-8238 [Electronic] United States
• PMID: 25798617 (Publication Type: Comparative Study, Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• FOXO3 protein, human
• Forkhead Box Protein O3
• Forkhead Transcription Factors
• Neoplasm Proteins
• RNA, Small Interfering
• MTOR protein, human
• AKT1 protein, human
• Casein Kinase I
• Proto-Oncogene Proteins c-akt
• TOR Serine-Threonine Kinases
• Oncogene Protein p21(ras)

Topics

• Amino Acid Sequence
• Animals
• Autophagy (physiology)
• Casein Kinase I (antagonists & inhibitors, physiology)
• Feedback, Physiological
• Fibroblasts (enzymology, physiology)
• Forkhead Box Protein O3
• Forkhead Transcription Factors (metabolism)
• Gene Expression Regulation, Neoplastic (genetics)
• Humans
• Mice
• Mice, Inbred BALB C
• Mice, Nude
• Molecular Sequence Data
• Neoplasm Proteins (physiology)
• Neoplasm Transplantation
• Neoplasms (enzymology)
• Oncogene Protein p21(ras) (physiology)
• Phosphatidylinositol 3-Kinases (physiology)
• Phosphorylation
• Protein Processing, Post-Translational
• Proto-Oncogene Proteins c-akt (physiology)
• RNA, Small Interfering (pharmacology)
• Sequence Alignment
• Sequence Homology, Amino Acid
• TOR Serine-Threonine Kinases (physiology)
• Transcriptional Activation