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Activation of the p62-Keap1-NRF2 pathway protects against ferroptosis in hepatocellular carcinoma cells.
Hepatology. 2016 Jan; 63(1):173-84.Hep

Abstract

Ferroptosis is a recently recognized form of regulated cell death caused by an iron-dependent accumulation of lipid reactive oxygen species. However, the molecular mechanisms regulating ferroptosis remain obscure. Here, we report that nuclear factor erythroid 2-related factor 2 (NRF2) plays a central role in protecting hepatocellular carcinoma (HCC) cells against ferroptosis. Upon exposure to ferroptosis-inducing compounds (e.g., erastin, sorafenib, and buthionine sulfoximine), p62 expression prevented NRF2 degradation and enhanced subsequent NRF2 nuclear accumulation through inactivation of Kelch-like ECH-associated protein 1. Additionally, nuclear NRF2 interacted with transcriptional coactivator small v-maf avian musculoaponeurotic fibrosarcoma oncogene homolog proteins such as MafG and then activated transcription of quinone oxidoreductase-1, heme oxygenase-1, and ferritin heavy chain-1. Knockdown of p62, quinone oxidoreductase-1, heme oxygenase-1, and ferritin heavy chain-1 by RNA interference in HCC cells promoted ferroptosis in response to erastin and sorafenib. Furthermore, genetic or pharmacologic inhibition of NRF2 expression/activity in HCC cells increased the anticancer activity of erastin and sorafenib in vitro and in tumor xenograft models.

CONCLUSION

These findings demonstrate novel molecular mechanisms and signaling pathways of ferroptosis; the status of NRF2 is a key factor that determines the therapeutic response to ferroptosis-targeted therapies in HCC cells.

Authors+Show Affiliations

Center for DAMP Biology, The Third Affiliated Hospital of Guangzhou Medical University, Guangzhou, Guangdong, China.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.Center for DAMP Biology, The Third Affiliated Hospital of Guangzhou Medical University, Guangzhou, Guangdong, China.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.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.

Pub Type(s)

Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

26403645

Citation

Sun, Xiaofang, et al. "Activation of the p62-Keap1-NRF2 Pathway Protects Against Ferroptosis in Hepatocellular Carcinoma Cells." Hepatology (Baltimore, Md.), vol. 63, no. 1, 2016, pp. 173-84.
Sun X, Ou Z, Chen R, et al. Activation of the p62-Keap1-NRF2 pathway protects against ferroptosis in hepatocellular carcinoma cells. Hepatology. 2016;63(1):173-84.
Sun, X., Ou, Z., Chen, R., Niu, X., Chen, D., Kang, R., & Tang, D. (2016). Activation of the p62-Keap1-NRF2 pathway protects against ferroptosis in hepatocellular carcinoma cells. Hepatology (Baltimore, Md.), 63(1), 173-84. https://doi.org/10.1002/hep.28251
Sun X, et al. Activation of the p62-Keap1-NRF2 Pathway Protects Against Ferroptosis in Hepatocellular Carcinoma Cells. Hepatology. 2016;63(1):173-84. PubMed PMID: 26403645.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Activation of the p62-Keap1-NRF2 pathway protects against ferroptosis in hepatocellular carcinoma cells. AU - Sun,Xiaofang, AU - Ou,Zhanhui, AU - Chen,Ruochan, AU - Niu,Xiaohua, AU - Chen,De, AU - Kang,Rui, AU - Tang,Daolin, Y1 - 2015/11/26/ PY - 2015/06/30/received PY - 2015/09/20/accepted PY - 2015/9/26/entrez PY - 2015/9/26/pubmed PY - 2016/5/11/medline SP - 173 EP - 84 JF - Hepatology (Baltimore, Md.) JO - Hepatology VL - 63 IS - 1 N2 - UNLABELLED: Ferroptosis is a recently recognized form of regulated cell death caused by an iron-dependent accumulation of lipid reactive oxygen species. However, the molecular mechanisms regulating ferroptosis remain obscure. Here, we report that nuclear factor erythroid 2-related factor 2 (NRF2) plays a central role in protecting hepatocellular carcinoma (HCC) cells against ferroptosis. Upon exposure to ferroptosis-inducing compounds (e.g., erastin, sorafenib, and buthionine sulfoximine), p62 expression prevented NRF2 degradation and enhanced subsequent NRF2 nuclear accumulation through inactivation of Kelch-like ECH-associated protein 1. Additionally, nuclear NRF2 interacted with transcriptional coactivator small v-maf avian musculoaponeurotic fibrosarcoma oncogene homolog proteins such as MafG and then activated transcription of quinone oxidoreductase-1, heme oxygenase-1, and ferritin heavy chain-1. Knockdown of p62, quinone oxidoreductase-1, heme oxygenase-1, and ferritin heavy chain-1 by RNA interference in HCC cells promoted ferroptosis in response to erastin and sorafenib. Furthermore, genetic or pharmacologic inhibition of NRF2 expression/activity in HCC cells increased the anticancer activity of erastin and sorafenib in vitro and in tumor xenograft models. CONCLUSION: These findings demonstrate novel molecular mechanisms and signaling pathways of ferroptosis; the status of NRF2 is a key factor that determines the therapeutic response to ferroptosis-targeted therapies in HCC cells. SN - 1527-3350 UR - https://www.unboundmedicine.com/medline/citation/26403645/Activation_of_the_p62_Keap1_NRF2_pathway_protects_against_ferroptosis_in_hepatocellular_carcinoma_cells_ L2 - https://doi.org/10.1002/hep.28251 DB - PRIME DP - Unbound Medicine ER -