Casein Kinase-1-Alpha Inhibitor (D4476) Sensitizes Microsatellite Instable Colorectal Cancer Cells to 5-Fluorouracil via Authophagy Flux Inhibition

• Published in: Archivum Immunologiae et Therapiae Experimentalis Vol. 69; no. 1; p. 26
• Main Authors: Siri, Morvarid, Behrouj, Hamid, Dastghaib, Sanaz, Zamani, Mozhdeh, Likus, Wirginia, Rezaie, Sedigheh, Hudecki, Jacek, Khazayel, Saeed, Łos, Marek J., Mokarram, Pooneh, Ghavami, Saeid
• Format: Journal Article
• Language: English
• Published: Cham Springer International Publishing 01.12.2021; Springer Nature B.V
• Subjects: 5-Fluorouracil; Apoptosis; Autophagy; Biomedical and Life Sciences; Biomedicine; c-Myc protein; Cancer; Cancer therapies; Casein; Casein kinase I; Casein Kinase Ialpha; Cell Line, Tumor; Cell proliferation; Chemoresistance; Chemotherapy; Colorectal cancer; Colorectal carcinoma; Colorectal Neoplasms - drug therapy; Colorectal Neoplasms - genetics; Cyclin D1; Drug resistance; Drug Resistance, Neoplasm - genetics; Enzyme inhibitors; Flow cytometry; Fluorouracil - pharmacology; G1 phase; Gene expression; Humans; Immunoblotting; Immunology; Kinases; Microsatellite Instability; Microsatellite Repeats; Myc protein; Original; Original Article; Phagocytosis; Pharmacology/Toxicology; Polymerase chain reaction; Casein kinase 1 alpha inhibitor; Combination treatment; 5-Fluorouracil; Autophagy; Colorectal cancer; Chemoresistance
• ISSN: 0004-069X; 1661-4917
• DOI: 10.1007/s00005-021-00629-2

Adjuvant chemotherapy with 5-fluorouracil (5-FU) does not improve survival of patients suffering from a form of colorectal cancer (CRC) characterized by high level of microsatellite instability (MSI-H). Given the importance of autophagy and multi-drug-resistant (MDR) proteins in chemotherapy resistance, as well as the role of casein kinase 1-alpha (CK1α) in the regulation of autophagy, we tested the combined effect of 5-FU and CK1α inhibitor (D4476) on HCT116 cells as a model of MSI-H colorectal cancer. To achieve this goal, the gene expression of Beclin1 and MDR genes, ABCG2 and ABCC3 were analyzed using quantitative real-time polymerase chain reaction. We used immunoblotting to measure autophagy flux (LC3, p62) and flow cytometry to detect apoptosis. Our findings showed that combination treatment with 5-FU and D4476 inhibited autophagy flux. Moreover, 5-FU and D4476 combination therapy induced G2, S and G1 phase arrests and it depleted mRNA of both cell proliferation-related genes and MDR-related genes ( ABCG2 , cyclin D1 and c-myc) . Hence, our data indicates that targeting of CK1α may increase the sensitivity of HCT116 cells to 5-FU. To our knowledge, this is the first description of sensitization of CRC cells to 5-FU chemotherapy by CK1α inhibitor. Graphic abstract