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PMPCB Silencing Sensitizes HCC Tumor Cells to Sorafenib Therapy
| Content Provider | Scilit |
|---|---|
| Author | Zheng, Jian-Feng He, Shaozhong Zeng, Zongyue Gu, Xinqi Cai, Lei Qi, Guangying |
| Copyright Year | 2019 |
| Description | Journal: Molecular Therapy Hepatocellular carcinoma (HCC) tumors invariably develop resistance to cytotoxic and targeted agents, resulting in failed treatment and tumor recurrence. Previous in vivo short hairpin RNA (shRNA) screening evidence revealed mitochondrial-processing peptidase (PMPC) as a leading gene contributing to tumor cell resistance against sorafenib, a multikinase inhibitor used to treat advanced HCC. Here, we investigated the contributory role of the β subunit of PMPC (PMPCB) in sorafenib resistance. Silencing PMPCB increased HCC tumor cell susceptibility to sorafenib therapy, decreased liver tumor burden, and improved survival of tumor-bearing mice receiving sorafenib. Moreover, sorafenib + PMPCB shRNA combination therapy led to attenuated liver tumor burden and improved survival outcome for tumor-bearing mice, and it reduced colony formation in murine and human HCC cell lines in vitro. Additionally, PMPCB silencing enhanced PINK1-Parkin signaling and downregulated the anti-apoptotic protein MCL-1 in sorafenib-treated HCC cells, which is indicative of a healthier pro-apoptotic phenotype. Higher pre-treatment MCL-1 expression was associated with inferior survival outcomes in sorafenib-treated HCC patients. Elevated MCL-1 expression was present in sorafenib-resistant murine HCC cells, while MCL-1 knockdown sensitized these cells to sorafenib. In conclusion, our findings advocate combination regimens employing sorafenib with PMPCB knockdown or MCL-1 knockdown to circumvent sorafenib resistance in HCC patients. |
| Related Links | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6822227/pdf http://www.cell.com/article/S1525001619303090/pdf |
| Ending Page | 1795 |
| Page Count | 12 |
| Starting Page | 1784 |
| ISSN | 15250016 |
| e-ISSN | 15250024 |
| DOI | 10.1016/j.ymthe.2019.06.014 |
| Journal | Molecular Therapy |
| Issue Number | 10 |
| Volume Number | 27 |
| Language | English |
| Publisher | Elsevier BV |
| Publisher Date | 2019-07-05 |
| Access Restriction | Open |
| Subject Keyword | Journal: Molecular Therapy Hepatocellular Carcinoma |
| Content Type | Text |
| Resource Type | Article |
| Subject | Genetics Medicine Drug Discovery Molecular Biology Molecular Medicine Pharmacology |
