Co-targeting p53-R249S and CDK4 synergistically suppresses survival of hepatocellular carcinoma cells. Issue 3 (3rd March 2020)

• Record Type: Journal Article
• Authors: Wang, Huai; Liao, Peng; Zeng, Shelya X.; Lu, Hua
• Is Part Of: Cancer biology & therapy. Volume 21:Issue 3(2020)
• Page Start: 269
• Page End: 277
• Publication Date: 2020-03-03
• Subjects: Synergistic effect -- PD-0332991 -- CP-31398 -- HCC -- p53-R249S -- CDK4/Cyclin D1 -- c-Myc; 616.99406
• DOI: 10.1080/15384047.2019.1685289
• Languages: English
• ISSNs: 1538-4047

Abstract

ABSTRACT: p53-R249S (p53-RS) is frequently detected in human hepatocellular carcinoma (HCC) that is highly associated with hepatitis B infection and aflatoxin B1 exposure. Our previous study showed that CDK4/Cyclin D1 phosphorylates p53-RS at the cancer-derived Ser249 and promotes its interaction with c-Myc in the nucleus, consequently enhancing c-Myc-dependent ribosomal biogenesis and HCC cell proliferation. Here we explored the possibility of co-targeting CDK4 and p53-RS with available small molecule inhibitors as a potential combined therapy for HCC that harbor p53-RS. Indeed, co-treatment of p53-RS-containing, but not wild-type p53 or p53-null, HCC cells with PD-0332991 (PD), a CDK4/6 inhibitor, and CP-31398 (CP), a compound that can restore the intrinsic conformation and transcriptional activity of mutant p53, drastically repressed the c-Myc activation function of p53-RS. This combination of PD with CP exhibited a synergistic effect on the inhibition of HCC cell growth in a p53-RS dependent manner, especially at a lower dose. These results suggest that co-targeting CDK4 and p53-RS can serve as a potential approach for the development of an effective therapy for HCC that harbor p53-RS.