期刊
CANCERS
卷 13, 期 23, 页码 -出版社
MDPI
DOI: 10.3390/cancers13236029
关键词
liver cancer; hepatocellular carcinoma; sorafenib; tyrosine kinase inhibitors; drug resistance; mitochondria; mitochondrial protein translation; mitochondrial ribosomal proteins; STAT3; OPB-111077
类别
资金
- Swiss National Science Foundation [SNSF-310030L_170182, SNSF-IZLSZ3_170898]
- Swiss Cancer League [KLS-4899-08-2019]
- Fondazione Ticinese Ricerca sul Cancro
Enhanced expression of mitochondrial ribosomal proteins and significant reprogramming of the mitochondrial network are associated with sorafenib resistance in human cell lines and hepatocarcinoma patients. This suggests potential actionable targets for improving therapeutic efficacy.
Simple Summary Enhanced expression of mitochondrial ribosomal proteins and marked reprogramming of the mitochondrial network are associated with sorafenib resistance in human cell lines and hepatocarcinoma patients, providing novel actionable targets for increasing therapeutic efficacy. The multi-kinase inhibitor sorafenib is a primary treatment modality for advanced-stage hepatocellular carcinoma (HCC). However, the therapeutic benefits are short-lived due to innate and acquired resistance. Here, we examined how HCC cells respond to sorafenib and adapt to continuous and prolonged exposure to the drug. Sorafenib-adapted HCC cells show a profound reprogramming of mitochondria function and marked activation of genes required for mitochondrial protein translation and biogenesis. Mitochondrial ribosomal proteins and components of translation and import machinery are increased in sorafenib-resistant cells and sorafenib-refractory HCC patients show similar alterations. Sorafenib-adapted cells also exhibited increased serine 727 phosphorylated (pSer727) STAT3, the prevalent form in mitochondria, suggesting that STAT3 might be an actionable target to counteract resistance. Consistently, a small-molecule STAT3 inhibitor reduces pSer727, reverts mitochondrial alterations, and enhances the response to sorafenib in resistant cells. These results sustain the importance of mitochondria plasticity in response to sorafenib and identify a clinically actionable strategy for improving the treatment efficacy in HCC patients.
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