The interplay between PRKCI/PKCλ/ι, SQSTM1/p62, and autophagy orchestrates the oxidative metabolic response that drives liver cancer

Abstract

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.

Keywords: Atypical PKCs; NRF2; autophagy; hepatocellular carcinoma; reactive oxygen species.

Figure 1.

PRKCI/PKCλ/ι suppresses liver cancer by inhibiting autophagy and metabolic reprogramming. PRKCI forms a ternary complex with SQSTM1 and LC3 to repress autophagy by direct phosphorylation of LC3’s S12. Loss of PRKCI unleashes autophagy that fuels the PPARA-driven oxidative program activated by PRKCI deficiency through the activation of PRKCZ/PKCζ, which culminates in the activation of the ROS-promoted NFE2L2 activation, critical for tumorigenesis.