Protein Kinase C (PKC) is a family of serine/threonine kinases that are involved in almost every signal transduction pathway. Their regulation is mediated by several factors and by binding to a group of scaffolding proteins called RACKs (Adams et al. 2011). The development of PKC modulators with anti-cancer therapeutic value is a major target in cancer. However, this task is made difficult because PKC has an important role to play in normal processes and the PKC family consists of at least 12 different isozymes. In colon cancer, there is differential expression of the PKC isozymes, giving the cancer cells a migratory advantage and thus promote cancer progression. Our hypothesis is that PKC expression, activity and localisation are altered as colon epithelial cells switch from normal to the transformed state. We are confident that being able to recognise these changes has the potential to be used as a biomarker and prognostic marker in the early detection of colon cancer. Using novel 3D culture techniques, we examined the gene expression pattern of the 12 different PKC isozymes. We found that the isozymes were differentially expressed and that their expression pattern changed depending on whether the cells were grown under 2-dimensional or 3-dimensional culture systems. Using patient samples, we also document differential expression of several isozymes when compared to matched normal tissue. Using a series of PKC activators, together with a series of synergistic cellular and molecular approaches, we follow the migration of specific PKC isoforms to the membrane fraction in cells. This migration is dependent on the expression of RACK1 as when we use siRNA against RACK1, we disrupt PKC translocation in colon cancer cells. Taken together, our findings confirm that there is differential expression of PKC isozymes in cancer cells. We also confirm that specific PKC isozymes colocalise with RACK1 at the membrane supporting our hypothesis that RACK1 plays a central role in translocating PKC in the colon epithelium. Differential PKC expression and PKC translocation may be an important mechanism regulating the transformed phenotype of colon cancer cells.
Citation Format: Catríona M. Dowling, Jennifer Hanly, Tara Dalton, Patrick A. Kiely. Correlating the expression of protein kinase C isozymes with the transformed phenotype in colorectal cancer. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 1393. doi:10.1158/1538-7445.AM2014-1393