Metallothionein-1 as a biomarker of altered redox metabolism in hepatocellular carcinoma cells exposed to sorafenib

Abstract

BackgroundSorafenib, a kinase inhibitor active against various solid tumours, induces oxidative stress and ferroptosis, a new form of oxidative necrosis, in some cancer cells. Clinically-applicable biomarkers that reflect the impact of sorafenib on the redox metabolism of cancer cells are lacking.MethodsWe used gene expression microarrays, real-time PCR, immunoblot, protein-specific ELISA, and gene reporter constructs encoding the enzyme luciferase to study the response of a panel of cancer cells to sorafenib. Tumour explants prepared from surgical hepatocellular carcinoma (HCC) samples and serum samples obtained from HCC patients receiving sorafenib were also used.ResultsWe observed that genes of the metallothionein-1 (MT1) family are induced in the HCC cell line Huh7 exposed to sorafenib. Sorafenib increased the expression of MT1G mRNA in a panel of human cancer cells, an effect that was not observed with eight other clinically-approved kinase inhibitors. We identified the minimal region of the MT1G promoter that confers inducibility by sorafenib to a 133 base pair region containing an Anti-oxidant Response Element (ARE) and showed the essential role of the transcription factor NRF2 (Nuclear factor erythroid 2-Related Factor 2). We examined the clinical relevance of our findings by analysing the regulation of MT1G in five tumour explants prepared from surgical HCC samples. Finally, we showed that the protein levels of MT1 increase in the serum of some HCC patients receiving sorafenib, and found an association with reduced overall survival.ConclusionThese findings indicate that MT1 constitute a biomarker adapted for exploring the impact of sorafenib on the redox metabolism of cancer cells.Electronic supplementary materialThe online version of this article (doi:10.1186/s12943-016-0526-2) contains supplementary material, which is available to authorized users.

Liver stage malaria infection is controlled by host regulators of lipid peroxidation

“…Thus, we asked if other inhibitors of this pathway also reduce parasite burden. Infected hepatocytes were treated with Sorafenib, another SLC7a11 inhibitor [33][34][35], which resulted in a similar decrease in parasite burden ( Fig. 4d, e).…”

Transcription Factor NRF2 as a Therapeutic Target for Chronic Diseases: A Systems Medicine Approach

“…For example, the epidermal growth factor receptor inhibitor erlotinib leads to NRF2 inhibition, participating in tumor cell sensation in nonsmall cell lung cancer (Xiaobo et al, 2016). The kinase cascade inhibitor sorafenib, used in therapy of hepatocellular carcinoma, also leads to inhibition of NRF2 and its downstream targets metallothionein-1 (Houessinon et al, 2016) and methylenetetrahydrofolate dehydrogenase 1 .…”

Ferroptosis-like signaling facilitates a potent innate defense againstPlasmodiuminfection

“…More recently, ferroptosis has been demonstrated to occur in other contexts [14][15][16][17] While Erastin treatment is the established method for inducing ferroptosis in culture, drug promiscuity could elicit off-target effects that confound the results. To minimize this possibility, we treated infected cultures with Sorafenib, another inducer of ferroptosis [18][19][20] and observed a similar result ( Fig. 1d, e).…”