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

TitlePKCλ/ι Loss Induces Autophagy, Oxidative Phosphorylation, and NRF2 to Promote Liver Cancer Progression.
Publication TypeJournal Article
Year of Publication2020
AuthorsKudo Y, Sugimoto M, Arias E, Kasashima H, Cordes T, Linares JF, Duran A, Nakanishi Y, Nakanishi N, L'Hermitte A, Campos A, Senni N, Rooslid T, Roberts LR, Cuervo AMaria, Metallo CM, Karin M, Diaz-Meco MT, Moscat J
JournalCancer Cell
Volume38
Issue2
Pagination247-262.e11
Date Published2020 08 10
ISSN1878-3686
KeywordsAnimals, Autophagy, Carcinoma, Hepatocellular, Cell Line, Cell Line, Tumor, Disease Progression, HEK293 Cells, Hep G2 Cells, Humans, Isoenzymes, Liver Neoplasms, Mice, Knockout, NF-E2-Related Factor 2, Oxidative Phosphorylation, Protein Kinase C, RNA Interference
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.

DOI10.1016/j.ccell.2020.05.018
Alternate JournalCancer Cell
PubMed ID32589943
PubMed Central IDPMC7423690
Grant ListR01 DK108743 / DK / NIDDK NIH HHS / United States
R01 CA218254 / CA / NCI NIH HHS / United States
R01 CA234245 / CA / NCI NIH HHS / United States
R01 DK124308 / DK / NIDDK NIH HHS / United States
R01 CA211794 / CA / NCI NIH HHS / United States
P30 CA030199 / CA / NCI NIH HHS / United States
P30 CA023100 / CA / NCI NIH HHS / United States
P30 AG038072 / AG / NIA NIH HHS / United States
R01 CA234128 / CA / NCI NIH HHS / United States
Related Faculty: 
Jorge Moscat, Ph.D. Juan Francisco Linares Rodriguez, Ph.D. Maria Diaz-Meco Conde, Ph.D.

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