title: Metallothionein-1G facilitates sorafenib resistance through inhibition of ferroptosis.
abstract: 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.
  
  
  
  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).
authors.affiliation: Center for DAMP Biology, The Third Affiliated Hospital of Guangzhou Medical University, Guangzhou, Guangdong, China.
authors.forename: Xiaofang
authors.initials: X
authors.lastname: Sun
authors.affiliation: Center for DAMP Biology, The Third Affiliated Hospital of Guangzhou Medical University, Guangzhou, Guangdong, China.
authors.forename: Xiaohua
authors.initials: X
authors.lastname: Niu
authors.affiliation: Department of Surgery, University of Pittsburgh Cancer Institute, University of Pittsburgh, Pittsburgh, PA.
authors.forename: Ruochan
authors.initials: R
authors.lastname: Chen
authors.affiliation: Center for DAMP Biology, The Third Affiliated Hospital of Guangzhou Medical University, Guangzhou, Guangdong, China.
authors.forename: Wenyin
authors.initials: W
authors.lastname: He
authors.affiliation: Center for DAMP Biology, The Third Affiliated Hospital of Guangzhou Medical University, Guangzhou, Guangdong, China.
authors.forename: De
authors.initials: D
authors.lastname: Chen
authors.affiliation: Department of Surgery, University of Pittsburgh Cancer Institute, University of Pittsburgh, Pittsburgh, PA.
authors.forename: Rui
authors.initials: R
authors.lastname: Kang
authors.affiliation: Center for DAMP Biology, The Third Affiliated Hospital of Guangzhou Medical University, Guangzhou, Guangdong, China.|Department of Surgery, University of Pittsburgh Cancer Institute, University of Pittsburgh, Pittsburgh, PA.
authors.forename: Daolin
authors.initials: D
authors.lastname: Tang
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents; D006528:Carcinoma, Hepatocellular / Q000378:metabolism*; D016923:Cell Death; D019008:Drug Resistance, Neoplasm; D056945:Hep G2 Cells; D006801:Humans; D008113:Liver Neoplasms / Q000378:metabolism*; D008668:Metallothionein / Q000378:metabolism*; D008819:Mice, Nude; D051267:NF-E2-Related Factor 2 / Q000378:metabolism; D009536:Niacinamide / Q000031:analogs & derivatives*; D010671:Phenylurea Compounds; D000077157:Sorafenib
chemical_list: D000970:Antineoplastic Agents; C499629:MT1G protein, human; D051267:NF-E2-Related Factor 2; C495635:NFE2L2 protein, human; D010671:Phenylurea Compounds; D009536:Niacinamide; D008668:Metallothionein; D000077157:Sorafenib