The retinoblastoma (Rb) protein regulates ferroptosis induced by sorafenib in human hepatocellular carcinoma cells.

Abstract

Sorafenib is the treatment of reference for advanced hepatocellular carcinoma (HCC), the most frequent form of primary liver tumour. The loss of function of the retinoblastoma (Rb) protein is an important event during liver carcinogenesis, but it is unclear whether the Rb status modulates the response of HCC cells to sorafenib. Here, we examined this question in HCC cells with reduced levels of Rb achieved through stable RNA interference. We show that HCC cells with reduced levels of Rb exhibit a two- to threefold increase in cell death induction upon exposure to sorafenib compared with controls. Sorafenib treatment of Balb/c nude mice that received tumour xenografts derived from HCC cells with reduced Rb levels resulted in complete tumour regression in 50% of the animals treated, compared with tumour stabilization in mice that received control cells. We show that, upon exposure to sorafenib, the Rb-negative status of HCC cells promotes the occurrence of ferroptosis, a form of oxidative necrosis. The findings highlight the role of Rb in the response of HCC cells to sorafenib and the regulation of ferroptosis.

• Authors: Christophe Louandre, Ingrid Marcq, Hicham Bouhlal, Emma Lachaier, Corinne Godin, Zuzana Saidak, Catherine François, Denis Chatelain, Véronique Debuysscher, Jean-Claude Barbare, Bruno Chauffert, Antoine Galmiche
• Journal: Cancer letters (Cancer Lett) Vol. 356 Issue 2 Pt B Pg. 971-7 (Jan 28 2015) ISSN: 1872-7980 [Electronic] Ireland
• PMID: 25444922 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.

Chemical References

• Antineoplastic Agents
• Phenylurea Compounds
• Reactive Oxygen Species
• Retinoblastoma Protein
• Niacinamide
• Sorafenib

Topics

• Animals
• Antineoplastic Agents (pharmacology)
• Apoptosis (drug effects)
• Blotting, Western
• Carcinoma, Hepatocellular (drug therapy, metabolism, pathology)
• Cell Proliferation (drug effects)
• Female
• Humans
• Liver Neoplasms (drug therapy, metabolism, pathology)
• Mice
• Mice, Inbred BALB C
• Mice, Nude
• Mitochondria (drug effects, metabolism, pathology)
• Necrosis
• Niacinamide (analogs & derivatives, pharmacology)
• Oxidative Stress (drug effects)
• Phenylurea Compounds (pharmacology)
• Reactive Oxygen Species (metabolism)
• Retinoblastoma Protein (metabolism)
• Sorafenib
• Tumor Cells, Cultured
• Xenograft Model Antitumor Assays