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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 b 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 proapoptotic phenotype. Higher pre-treatment MCL-1 expression was associated with inferior survival outcomes in sorafenibtreated 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.

Esterases are biocatalysts in food industry aimed for nutrition improvements, formation of flavor, and food fermentation. Two esterases EstGX1 and EstGX2 were identified based on function-based screening of a soil metagenomic cosmid library. Enzyme properties including optimum pH, optimal temperature, tolerance to organic solvents and metal ions were measured, respectively. The activity of EstGX2 could maintain about 40% after incubated at 99℃ for 55 min, and could be increased in presence of 15% ethanol. The unique properties of EstGX2, high thermostability and stability in the presence of several organic solvents, may make it a promising enzyme candidate in food industry.

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