Activation of the p62-Keap1-NRF2 pathway protects against ferroptosis in hepatocellular carcinoma cells.

Abstract

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.

• Authors: Xiaofang Sun, Zhanhui Ou, Ruochan Chen, Xiaohua Niu, De Chen, Rui Kang, Daolin Tang
• Journal: Hepatology (Baltimore, Md.) (Hepatology) Vol. 63 Issue 1 Pg. 173-84 (Jan 2016) ISSN: 1527-3350 [Electronic] United States
• PMID: 26403645 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: © 2015 by the American Association for the Study of Liver Diseases.

Chemical References

• Intracellular Signaling Peptides and Proteins
• KEAP1 protein, human
• Kelch-Like ECH-Associated Protein 1
• NF-E2-Related Factor 2
• NFE2L2 protein, human
• P62 protein, human
• RNA-Binding Proteins
• Iron

Topics

• Animals
• Carcinoma, Hepatocellular (metabolism, pathology)
• Cell Death (physiology)
• Humans
• Intracellular Signaling Peptides and Proteins (physiology)
• Iron (physiology)
• Kelch-Like ECH-Associated Protein 1
• Liver Neoplasms (metabolism, pathology)
• Mice
• Mice, Inbred C57BL
• NF-E2-Related Factor 2 (physiology)
• RNA-Binding Proteins (physiology)
• Signal Transduction
• Tumor Cells, Cultured