Atypical Protein Kinase C{iota} (PKC{iota}) Promotes Metastasis of Esophageal Squamous Cell Carcinoma by Enhancing Resistance to Anoikis via PKC{iota}-SKP2-AKT Pathway.

摘要

Protein kinase Ciota (PKCiota) is an atypical PKC isoform and participates in multiple aspects of the transformed phenotype in human cancer cells. We previously reported that frequent amplification and overexpression of PKCiota were correlated with lymph node metastasis in primary esophageal squamous cell carcinomas (ESCC). In the present study, short interfering RNA-mediated silencing of PKCiota revealed that this enzyme was required for cell migration, invasion, and resistance to anoikis. In vivo experiments showed that PKCiota suppression decreased tumor growth in esophageal cancer xenografts and lung metastases in nude mice. At the molecular level, knockdown of PKCiota in suspended ESCC cells caused a decrease in S-phase kinase-associated protein 2 (SKP2) that had been reported to promote resistance to anoikis via the PI3K/AKT pathway. AKT phosphorylation was abolished after PKCiota suppression, but AKT activation could be refreshed by PKCiota upregulation, suggesting that PKCiota enhanced cell resistance to anoikis via the PKCiota-SKP2-PI3K/AKT pathway. Addition of the proteasome inhibitor MG132 prevented the decrease of SKP2 in PKCiota silenced cells, and polyubiquitin-SKP2 was elevated after PKCiota depletion, showing that PKCiota might regulate the expression of SKP2 through the ubiquitin-proteasome pathway in suspended cells. Furthermore, overexpression of SKP2 in PKCiota-downregulated cells restored cell resistance to anoikis. Most importantly, PKCiota expression significantly correlated with SKP2 in 133 ESCC tissues (P = 0.031). Taken together, our data show that PKCiota promotes tumorigenicity and metastasis of human esophageal cancer and that SKP2 is a candidate downstream effector of PKCiota signaling in ESCC. Mol Cancer Res; 9(4); 390-402. (c)2011 AACR.