Functional Analysis Of Atypical Protein Kinase C_ι (PKC_ι) In Esophageal Squamous Cell Cacrinoma

We have previously shown that atypical protein kinase C1(PKC1) is an oncoprotein in esophageal squamous cell carcinomas (ESCC). However, the mechanisms underlying the role of PKCl in this disease remain unclear. In the present work, we found that inhibition of PKCl expression by RNAi induced apoptosis via down-regulation of P-catenin in esophageal cancer cells. We also showed that depletion of PKCl activated autophagy via the elevation of intracellular ROS levels. Down-regulation of P-catenin induced by knockdown of PKCi could be rescued by autophagy inhibition. Additionally, forced expression of PKCl protected P-catenin from autophagic degradation in the presence of autophagy inducers, which suggested that PKCl regulated the stability of P-catenin through an autophagy-dependent pathway. Immunoprecipitation assays showed that knockdown of PKCl increased poly-ubiquitinated-β-catenin levels and promoted interactions between P-catenin and the autophagosome marker LC3. Importantly, we observed that PKCl was positively correlated with P-catenin and the autophagic substrate p62in primary esophageal cancer tissues. Furthermore, we showed that a PKCl-and LC3-interacting protein Hsc70was required for PKCl knockdown-mediated P-catenin degradation. We also found that PKCl negatively regulated the ubiquitin E3ligase RNF111, which was responsible for P-catenin ubiquitination induced by PKCl knockdown. These results indicated that PKCl-regulated autophagy suppression and P-catenin stability were functionally important mechanisms underlying ESCC cell survival. These data provide new insights into PKCl signaling in human cancer.