PMPCB Silencing Sensitizes HCC Tumor Cells to Sorafenib Therapy

• Published in: Molecular therapy Vol. 27; no. 10; pp. 1784 - 1795
• Main Authors: Zheng, Jian-feng, He, Shaozhong, Zeng, Zongyue, Gu, Xinqi, Cai, Lei, Qi, Guangying
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 02.10.2019; Elsevier Limited; American Society of Gene & Cell Therapy
• Subjects: Animals; Apoptosis; beta-MPP; Carcinoma, Hepatocellular - drug therapy; Carcinoma, Hepatocellular - genetics; Carcinoma, Hepatocellular - metabolism; Carcinoma, Hepatocellular - pathology; Cell Line, Tumor; Cell Proliferation - drug effects; Cell Survival - drug effects; Cytotoxicity; Drug Resistance, Neoplasm - drug effects; Drug Synergism; Experiments; FDA approval; Gene Expression Regulation, Neoplastic - drug effects; HCC; Hepatocellular carcinoma; Humans; Kinases; Laboratory animals; Liver cancer; Liver Neoplasms - drug therapy; Liver Neoplasms - genetics; Liver Neoplasms - metabolism; Liver Neoplasms - pathology; MCL-1; Mcl-1 protein; Medical prognosis; Metalloendopeptidases - antagonists & inhibitors; Metalloendopeptidases - genetics; Metalloendopeptidases - metabolism; Mice; Mitochondria; Mitochondrial Processing Peptidase; Mitochondrial Proteins - antagonists & inhibitors; Mitochondrial Proteins - genetics; Mitochondrial Proteins - metabolism; MPPB; Mutation; Myeloid Cell Leukemia Sequence 1 Protein - genetics; Myeloid Cell Leukemia Sequence 1 Protein - metabolism; Original; Parkin; Parkin protein; Peptidase; Phenotypes; PINK1; PMPCB; Protein expression; Proteins; PTEN-induced putative kinase; Ribonucleic acid; RNA; RNA, Small Interfering - administration & dosage; RNA, Small Interfering - pharmacology; Signal Transduction - drug effects; sorafenib; Sorafenib - administration & dosage; Sorafenib - pharmacology; Survival Analysis; Targeted cancer therapy; Tumor cells; Tumors; Xenograft Model Antitumor Assays; United States > US; MPPB; PINK1; sorafenib; MCL-1; beta-MPP; HCC; PMPCB; hepatocellular carcinoma; Parkin
• ISSN: 1525-0016; 1525-0024
• DOI: 10.1016/j.ymthe.2019.06.014

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. Zheng et al. demonstrate that silencing the β subunit of PMPC (PMPCB) increases HCC tumor cell susceptibility to sorafenib therapy, decreases liver tumor burden, and improves survival of tumor-bearing mice receiving sorafenib. Moreover, PMPCB silencing enhances PINK1-Parkin signaling and downregulates the anti-apoptotic protein MCL-1 in sorafenib-treated HCC cells, indicative of a healthier, pro-apoptotic phenotype.