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PKCλ/ι Loss Induces Autophagy, Oxidative Phosphorylation, and NRF2 to Promote Liver Cancer Progression

Authors :
Hiroaki Kasashima
Masayuki Sugimoto
Thekla Cordes
Antoine L’Hermitte
Naoko Nakanishi
Tarmo Rooslid
Alex Campos
Michael Karin
Ana Maria Cuervo
Esperanza Arias
Jorge Moscat
Nadia Senni
Yotaro Kudo
Juan F. Linares
Lewis R. Roberts
Christian M. Metallo
Maria T. Diaz-Meco
Yuki Nakanishi
Angeles Duran
Source :
Cancer Cell. 38:247-262.e11
Publication Year :
2020
Publisher :
Elsevier BV, 2020.

Abstract

Oxidative stress plays a critical role in liver tissue damage and in hepatocellular carcinoma (HCC) initiation and progression. However, the mechanisms that regulate autophagy and metabolic reprogramming during reactive oxygen species (ROS) generation, and how ROS promote tumorigenesis, still need to be fully understood. We show that protein kinase C (PKC) λ/ι loss in hepatocytes promotes autophagy and oxidative phosphorylation. This results in ROS generation, which through NRF2 drives HCC through cell-autonomous and non-autonomous mechanisms. Although PKCλ/ι promotes tumorigenesis in oncogene-driven cancer models, emerging evidence demonstrate that it is a tumor suppressor in more complex carcinogenic processes. Consistently, PKCλ/ι levels negatively correlate with HCC histological tumor grade, establishing this kinase as a tumor suppressor in liver cancer.

Details

ISSN :
15356108
Volume :
38
Database :
OpenAIRE
Journal :
Cancer Cell
Accession number :
edsair.doi.dedup.....3564b693b42ac3915532746cf974a0e4
Full Text :
https://doi.org/10.1016/j.ccell.2020.05.018