TY - JOUR
T1 - Metallothionein-1G facilitates sorafenib resistance through inhibition of ferroptosis
AU - Sun, Xiaofang
AU - Niu, Xiaohua
AU - Chen, Ruochan
AU - He, Wenyin
AU - Chen, De
AU - Kang, Rui
AU - Tang, Daolin
N1 - Publisher Copyright:
© 2016 by the American Association for the Study of Liver Diseases.
PY - 2016/8/1
Y1 - 2016/8/1
N2 - 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).
AB - 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).
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U2 - 10.1002/hep.28574
DO - 10.1002/hep.28574
M3 - Article
C2 - 27015352
AN - SCOPUS:84978997718
SN - 0270-9139
VL - 64
SP - 488
EP - 500
JO - Hepatology
JF - Hepatology
IS - 2
ER -