Title | PKCλ/ι Loss Induces Autophagy, Oxidative Phosphorylation, and NRF2 to Promote Liver Cancer Progression. |
Publication Type | Journal Article |
Year of Publication | 2020 |
Authors | Kudo 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 |
Journal | Cancer Cell |
Volume | 38 |
Issue | 2 |
Pagination | 247-262.e11 |
Date Published | 2020 08 10 |
ISSN | 1878-3686 |
Keywords | Animals, 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. |
DOI | 10.1016/j.ccell.2020.05.018 |
Alternate Journal | Cancer Cell |
PubMed ID | 32589943 |
PubMed Central ID | PMC7423690 |
Grant List | R01 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.