Abstract
Sorafenib is the first line treatment for advanced hepatocellular carcinoma (HCC). We explored its impact on the proteostasis of cancer cells, i.e. the processes that regulate the synthesis, maturation and turn-over of cellular proteins. We observed that sorafenib inhibits the production of the tumour marker alpha-foetoprotein (AFP) in two different HCC cell lines, an effect that correlated with a radical inhibition of protein biosynthesis. This effect was observed at clinically relevant concentrations of sorafenib and was not related to the effect of sorafenib on the transport of amino acids across the plasma membrane or the induction of the unfolded protein response (UPR). Instead, we observed that sorafenib inhibits translation initiation and the mechanistic target of rapamycin (mTOR) signaling cascade, as shown by the analysis of phosphorylation levels of the protein 4EBP1 (eukaryotic translation initiation factor 4E binding protein 1). We explored the consequences of this inhibition in HCC cells. We observed that overall sorafenib is a weak inducer of the UPR that can paradoxically prevent the UPR induced by tunicamycin. We also found no direct synergistic anticancer effect between sorafenib and various strategies that inhibit the UPR. In agreement with the possibility that translation inhibition might be an adaptive stress response in HCC cells, we noted that it protects cancer cell from ferroptosis, a form of oxidative necrosis. Our findings point to the modulation of protein biosynthesis and mTOR signaling as being important, yet complex determinants of the response of HCC cells to sorafenib.
Highlights
Hepatocellular carcinoma (HCC), the most frequent form of primary liver tumour, remains a major cause of cancer-associated deaths worldwide [1]
We explored the impact of sorafenib, the medical treatment of reference for hepatocellular carcinoma (HCC), on the proteostasis of cancer cells
We observed that sorafenib strongly inhibits AFP production and protein biosynthesis in different HCC cell lines and a variety of eukaryotic cells
Summary
Hepatocellular carcinoma (HCC), the most frequent form of primary liver tumour, remains a major cause of cancer-associated deaths worldwide [1]. Adjibade et al reported that sorafenib promotes the formation of stress granules, i.e. cytoplasmic bodies formed under conditions of stalled translation in cancer cells [11]. Sorafenib appears to be potentially able to interfere with all steps of protein production, chaperoning, folding and turn-over in cancer cells. While sorafenib has been reported to inhibit protein synthesis and lead to the formation of stress granules in HCC cells [11], a link to translation regulation has not yet been established. It is unclear to which extent the inhibition of protein synthesis relates to the anti-oncogenic efficacy of sorafenib, and in particular to its effect on the two essential kinases ERK and mTOR (mechanistic target of rapamycin) [16]
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