Mitochondrial plasticity promotes resistance to sorafenib and vulnerability to STAT3 inhibition in human hepatocellular carcinoma
Additional information
Authors
Pandit S. K.,
Sandrini G.,
Merulla J.,
Nobili V.,
Wang X.,
Zangari A.,
Rinaldi A.,
Shinde D.,
Carbone G.,
Catapano C.
Type
Journal Article
Year
2021
Language
English
Abstract
The multi-kinase inhibitor sorafenib is a primary treatment modality for advanced-stagehepatocellular carcinoma (HCC). However, the therapeutic benefits are short-lived due to innateand acquired resistance. Here, we examined how HCC cells respond to sorafenib and adapt tocontinuous and prolonged exposure to the drug. Sorafenib-adapted HCC cells show a profoundreprogramming of mitochondria function and marked activation of genes required for mitochondrialprotein translation and biogenesis. Mitochondrial ribosomal proteins and components of translationand import machinery are increased in sorafenib-resistant cells and sorafenib-refractory HCC patientsshow similar alterations. Sorafenib-adapted cells also exhibited increased serine 727 phosphorylated(pSer727) STAT3, the prevalent form in mitochondria, suggesting that STAT3 might be an actionabletarget to counteract resistance. Consistently, a small-molecule STAT3 inhibitor reduces pSer727,reverts mitochondrial alterations, and enhances the response to sorafenib in resistant cells. Theseresults sustain the importance of mitochondria plasticity in response to sorafenib and identify aclinically actionable strategy for improving the treatment efficacy in HCC patients.
Keywords
Liver cancer, Hepatocellular carcinoma, Sorafenib, Tyrosine kinase inhibitors, Drug resistance, Mitochondria, Mitochondrial protein translation, Mitochondrial ribosomal proteins, STAT3, OPB-111077
Journal
Cancers
Volume
13
Number ( Month )
23
Pages (or article number)
6029
Diffusion
License
CC BY
Visibility
Public
Status open access
Gold
