Casein kinase ۱a regulates autophagy flux through AKT/phospho-β-catenin (S۵۵۲) axis in HCT۱۱۶, a RAS-mutated colorectal cancer cell line

Introduction: The Wnt/β-catenin pathway, which interferes with cell proliferation, differentiation, and autophagy, is commonly dysregulated in colorectal cancer (CRC). Mutation of the RAS oncogene is the most prevalent genetic alteration in CRC and has been linked to activation of protein kinase B (AKT) signaling. Phosphorylation of β-catenin at Ser ۵۵۲ by AKT contributes to β-catenin stability, transcriptional activity, and increase of cell proliferation. Casein kinase ۱ alpha (CK۱a) is an enzyme that simultaneously regulates Wnt/β-catenin and AKT. The link of the AKT and Wnt pathway to autophagy in RAS-mutated CRC cells has not well identified. Therefore, we investigated how pharmacological CK۱a inhibition (D۴۴۷۶) is involved in regulation of autophagy, Wnt/β-catenin, and AKT pathways in RAS-mutated CRC cell lines. Methods: Western blotting was used to detect AKT, phospho-AKT (S۴۷۳), β-catenin, phospho-β-catenin (S۵۵۲), p۶۲, and LC۳βII protein abundance; GAPDH expression was used for normalization. Results: Our results showed that D۴۴۷۶ significantly reduced the AKT/phospho-β-catenin (S۵۵۲) axis concomitantly with autophagy flux inhibition in RAS-mutated CRC cells. Conclusion: Our results indicate that CK۱a inhibition reduces autophagy flux and promotes apoptosis by interfering with the AKT/phospho-β-catenin (S۵۵۲) axis in RAS-mutated CRC cells.

کلیدواژه ها:

RAS oncogene ، casein kinase ۱a ، autophagy ، AKT pathway ، phospho-β-catenin (S۵۵۲)