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

Cancer Cell. 2020 Aug 10;38(2):247-262.e11. doi: 10.1016/j.ccell.2020.05.018. | PubMed

Yotaro Kudo¹, Masayuki Sugimoto², Esperanza Arias³, Hiroaki Kasashima¹, Thekla Cordes⁴, Juan F Linares⁵, Angeles Duran⁵, Yuki Nakanishi¹, Naoko Nakanishi¹, Antoine L'Hermitte¹, Alex Campos¹, Nadia Senni¹, Tarmo Rooslid¹, Lewis R Roberts⁶, Ana Maria Cuervo³, Christian M Metallo⁴, Michael Karin⁷, Maria T Diaz-Meco⁵, Jorge Moscat⁸

1. Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA 92037, USA.
2. Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA 92037, USA; Laboratory for Advanced Medicine Research, SHIONOGI & CO., LTD., 3-1-1, Futaba-cho, Toyonaka, 561-0825, Japan.
3. Departments of Medicine and of Developmental and Molecular Biology and Institute for Aging Studies, Albert Einstein College of Medicine, Bronx, NY 10461, USA.
4. Department of Bioengineering, Moores Cancer Center, University of California, San Diego, La Jolla, CA 92093, USA.
5. Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA 92037, USA; Department of Pathology and Laboratory Medicine, Weill Cornell Medicine, 1300 York Avenue, New York, NY 10065, USA.
6. Division of Gastroenterology and Hepatology, Mayo Clinic College of Medicine, Rochester, MN 55905, USA.
7. Laboratory of Gene Regulation and Signal Transduction, Departments of Pharmacology and Pathology, Moores Cancer Center, University of California, San Diego, CA 92093-0987, USA.
8. Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA 92037, USA; Department of Pathology and Laboratory Medicine, Weill Cornell Medicine, 1300 York Avenue, New York, NY 10065, USA. Electronic address: jom4010@med.cornell.edu.

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.

Presented By Yotaro Kudo