|The interplay between PRKCI/PKCλ/ι, SQSTM1/p62, and autophagy orchestrates the oxidative metabolic response that drives liver cancer.
|Year of Publication
|Moscat J, Diaz-Meco MT
|Autophagy, Carcinoma, Hepatocellular, Humans, Kelch-Like ECH-Associated Protein 1, Liver Neoplasms, NF-E2-Related Factor 2, Oxidative Phosphorylation, Oxidative Stress, Sequestosome-1 Protein
Hepatocellular carcinoma (HCC) is the consequence of chronic liver damage caused by the excessive generation of reactive oxygen species (ROS). To mitigate the deleterious effects of ROS, cells activate the transcription factor NFE2L2/NRF2, which is constitutively degraded through its partner KEAP1. The inactivation of KEAP1 by ROS results in the upregulation of NFE2L2, which leads to the upregulation of critical detoxifying molecules that serve to keep ROS at tolerable levels in order to maintain cell viability. It is thought that this mechanism allows cells to accumulate mutations, which together with the additional pro-tumorigenic and pro-survival effects of NFE2L2 activation, promote cancer initiation and progression. Germane to this phenomenon is macroautophagy/autophagy, which under homeostatic conditions has also been proposed to serve as a detoxifying mechanism by clearing up toxic aggregates and damaged organelles. Our recent data establish a new paradigm for the role that autophagy plays in HCC development.
|PubMed Central ID
|R01 CA211794 / CA / NCI NIH HHS / United States
R01 CA218254 / CA / NCI NIH HHS / United States
R01 DK108743 / DK / NIDDK NIH HHS / United States
Jorge Moscat, Ph.D. Maria Diaz-Meco Conde, Ph.D.