J Cancer 2022; 13(11):3234-3243. doi:10.7150/jca.76618 This issue Cite

Research Paper

Combination of Metformin and Sorafenib Induces Ferroptosis of Hepatocellular Carcinoma Through p62-Keap1-Nrf2 Pathway

Kezhong Tang1, Qing Chen1, Yanmo Liu2, Lantian Wang1, Wenjie Lu1✉

1. Department of Surgery, The Second Affiliated Hospital, Zhejiang University School of Medicine, #88 Jiefang Road, Hangzhou 310009, PR China.
2. Department of Pharmacy, Affiliated Sir RunRun Shaw Hospital, Zhejiang University School of Medicine, Hangzhou 310009, PR China.

Citation:
Tang K, Chen Q, Liu Y, Wang L, Lu W. Combination of Metformin and Sorafenib Induces Ferroptosis of Hepatocellular Carcinoma Through p62-Keap1-Nrf2 Pathway. J Cancer 2022; 13(11):3234-3243. doi:10.7150/jca.76618. https://www.jcancer.org/v13p3234.htm
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Abstract

Graphic abstract

Hepatocellular carcinoma (HCC) is one of the most lethal cancers in the world. Sorafenib is the first small-molecule multi-kinase inhibitors approved by FDA for treatment of advanced HCC. Metformin has been demonstrated to have benefit for preventing cancer progression. In human recurrent HCCs, NF-E2-related factor 2 (Nrf2) was overexpressed and associated with poor survival. Nrf2 related signaling pathway plays central role to mediate cellular resistance to sorafenib through protecting HCC cells from ferroptosis. The effect of Combination treatment for HCC cells and the intrinsic mechanism have not been reported. In this study, metformin augmented the anti-tumor effect of sorafenib for HCC through ferroptosis induction by inhibiting Nrf2 related pathway. Based on the results of Nrf2 knockdown and p62 knockdown study, the combination of sorafenib and metformin suppressed proliferation of HCC cells through p62-Keap1-Nrf2/HO1 signaling way. Size of xenografts treated with the combination of sorafenib and metformin was smaller than other groups in vivo. Moreover, the combination treatment greatly induced ferroptosis in HCC cells through inhibiting Nrf2 expression. Based on our findings, the combination treatment suppressed proliferation of HCC cells through ferroptosis induction, by p62-Keap1-Nrf2/HO1 signaling way.

Keywords: Hepatocellular carcinoma (HCC), sorafenib, metformin, ferroptosis, NF-E2-related factor 2 (Nrf2)


Citation styles

APA
Tang, K., Chen, Q., Liu, Y., Wang, L., Lu, W. (2022). Combination of Metformin and Sorafenib Induces Ferroptosis of Hepatocellular Carcinoma Through p62-Keap1-Nrf2 Pathway. Journal of Cancer, 13(11), 3234-3243. https://doi.org/10.7150/jca.76618.

ACS
Tang, K.; Chen, Q.; Liu, Y.; Wang, L.; Lu, W. Combination of Metformin and Sorafenib Induces Ferroptosis of Hepatocellular Carcinoma Through p62-Keap1-Nrf2 Pathway. J. Cancer 2022, 13 (11), 3234-3243. DOI: 10.7150/jca.76618.

NLM
Tang K, Chen Q, Liu Y, Wang L, Lu W. Combination of Metformin and Sorafenib Induces Ferroptosis of Hepatocellular Carcinoma Through p62-Keap1-Nrf2 Pathway. J Cancer 2022; 13(11):3234-3243. doi:10.7150/jca.76618. https://www.jcancer.org/v13p3234.htm

CSE
Tang K, Chen Q, Liu Y, Wang L, Lu W. 2022. Combination of Metformin and Sorafenib Induces Ferroptosis of Hepatocellular Carcinoma Through p62-Keap1-Nrf2 Pathway. J Cancer. 13(11):3234-3243.

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