Co-targeting p53-R249S and CDK4 synergistically suppresses survival of hepatocellular carcinoma cells
dc.contributor.author | Wang, H | |
dc.contributor.author | Liao, P | |
dc.contributor.author | Zeng, SX | |
dc.contributor.author | Lu, H | |
dc.coverage.spatial | United States | |
dc.date.accessioned | 2023-12-05T20:07:19Z | |
dc.date.available | 2023-12-05T20:07:19Z | |
dc.date.issued | 2020-03-03 | |
dc.identifier.issn | 1538-4047 | |
dc.identifier.issn | 1555-8576 | |
dc.identifier.uri | https://www.ncbi.nlm.nih.gov/pubmed/31747859 | |
dc.identifier.uri | https://hdl.handle.net/2027.42/191685 | en |
dc.description.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. | |
dc.format.medium | Print-Electronic | |
dc.language | eng | |
dc.publisher | Taylor & Francis | |
dc.subject | CDK4/Cyclin D1 | |
dc.subject | CP-31398 | |
dc.subject | HCC | |
dc.subject | PD-0332991 | |
dc.subject | Synergistic effect | |
dc.subject | c-Myc | |
dc.subject | p53-R249S | |
dc.subject | Apoptosis | |
dc.subject | Biomarkers, Tumor | |
dc.subject | Carcinoma, Hepatocellular | |
dc.subject | Cell Proliferation | |
dc.subject | Cyclin-Dependent Kinase 4 | |
dc.subject | Drug Synergism | |
dc.subject | Drug Therapy, Combination | |
dc.subject | Gene Expression Regulation, Neoplastic | |
dc.subject | Humans | |
dc.subject | Liver Neoplasms | |
dc.subject | Mutation | |
dc.subject | Phosphorylation | |
dc.subject | Piperazines | |
dc.subject | Protein Kinase Inhibitors | |
dc.subject | Pyridines | |
dc.subject | Pyrimidines | |
dc.subject | Tumor Cells, Cultured | |
dc.subject | Tumor Suppressor Protein p53 | |
dc.title | Co-targeting p53-R249S and CDK4 synergistically suppresses survival of hepatocellular carcinoma cells | |
dc.type | Article | |
dc.identifier.pmid | 31747859 | |
dc.description.bitstreamurl | http://deepblue.lib.umich.edu/bitstream/2027.42/191685/2/Co-targeting p53-R249S and CDK4 synergistically suppresses survival of hepatocellular carcinoma cells.pdf | |
dc.identifier.doi | 10.1080/15384047.2019.1685289 | |
dc.identifier.doi | https://dx.doi.org/10.7302/21865 | |
dc.identifier.source | Cancer Biology and Therapy | |
dc.description.version | Published version | |
dc.date.updated | 2023-12-05T20:07:11Z | |
dc.identifier.orcid | 0000-0002-8409-5574 | |
dc.description.filedescription | Description of Co-targeting p53-R249S and CDK4 synergistically suppresses survival of hepatocellular carcinoma cells.pdf : Published version | |
dc.identifier.volume | 21 | |
dc.identifier.issue | 3 | |
dc.identifier.startpage | 269 | |
dc.identifier.endpage | 277 | |
dc.identifier.name-orcid | Wang, H | |
dc.identifier.name-orcid | Liao, P; 0000-0002-8409-5574 | |
dc.identifier.name-orcid | Zeng, SX | |
dc.identifier.name-orcid | Lu, H | |
dc.working.doi | 10.7302/21865 | en |
dc.owningcollname | Surgery, Department of |
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