Metallothionein-1G Facilitates Sorafenib Resistance through Inhibition of Ferroptosis

By Xiaofang Sun, X. Niu, Ruochan Chen, Wenyin He, De Chen, R. Kang, D. Tang. Hepatology, 2016

626 citations recorded by the source corpus.

Hepatocellular carcinoma (HCC) is a major cause of cancer‐related death worldwide and currently has the fastest rising incidence of all cancers. Sorafenib was originally identified as an inhibitor of multiple oncogenic kinases and remains the only approved systemic therapy for advanced HCC. However, acquired resistance to sorafenib has been found in HCC patients, which results in poor prognosis. Here, we show that metallothionein (MT)‐1G is a critical regulator and promising therapeutic target of sorafenib resistance in human HCC cells. The expression of MT‐1G messenger RNA and protein is remarkably induced by sorafenib but not other clinically relevant kinase inhibitors (e.g., erlotinib, gefitinib, tivantinib, vemurafenib, selumetinib, imatinib, masitinib, and ponatinib). Activation of the transcription factor nuclear factor erythroid 2‐related factor 2, but not p53 and hypoxia‐inducible factor 1‐alpha, is essential for induction of MT‐1G expression following sorafenib treatment. Importantly, genetic and pharmacological inhibition of MT‐1G enhances the anticancer activity of sorafenib in vitro and in tumor xenograft models. The molecular mechanisms underlying the action of MT‐1G in sorafenib resistance involve the inhibition of ferroptosis, a novel form of regulated cell death. Knockdown of MT‐1G by RNA interference increases glutathione depletion and lipid peroxidation, which contributes to sorafenib‐induced ferroptosis. Conclusion: These findings demonstrate a novel molecular mechanism of sorafenib resistance and suggest that MT‐1G is a new regulator of ferroptosis in HCC cells. (Hepatology 2016;64:488‐500)

Subfields: Nutrition and Dietetics, Pathology and Forensic Medicine, Pulmonary and Respiratory Medicine

View Paper: https://www.semanticscholar.org/paper/b698d57b0c4cf1bdc936c3dfde2f440aab5b623d

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Citations in the corpus

Molecular mechanisms of cell death: recommendations of the Nomenclature Committee on Cell Death 2018 (2018, background): “Additional ferroptosis regulators described so far include: (1) the mevalonate pathway component farnesyldiphosphate farnesyltransferase 1 (FDFT1; best known as SQS) [545]; (2) the transsulfuration pathway enzyme cysteinyl-tRNA synthetase (CARS) [578]; (3) heat shock protein family B (small) member ”
The Tumor Suppressor Protein p53 and the Ferroptosis Network (2018, positive): “We identified metallothionein-1 G (a cysteine residue-rich protein) as a direct NFE2L2 target gene contributing to ferroptosis resistance [47].”
Ferroptosis: molecular mechanisms and health implications (2020, background): “Besides quinone oxidoreductase 1 (NQO1) and HMOX1, metallothionein 1G (MT1G) was identified as a new NFE2L2targeted gene, which can drive ferroptosis resistance in HCC cells.(127) The discovery of a large number of NFE2L2 target genes (e.”
The molecular machinery of regulated cell death (2019, background): “NFE2L2-mediated transactivation of metallothionein 1G (MT1G, a cysteine-rich protein with a high affinity for divalent heavy metal ions), SLC7A11, and heme oxygenase 1 (HMOX1) limits ferroptosis.(143,147,148) However, upon excessive activation of NRF2, HMOX1 gets hyperactivated and induces ferroptos”
Ferroptosis in cancer therapy: a novel approach to reversing drug resistance (2022, background): “Inhibition of MT-1G expression enhances the anticancer activity of sorafenib by ferroptosis induction both in vitro and in vivo [45].”