Protein kinase C beta II suppresses colorectal cancer by regulating IGF-1 mediated cell survival
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Catríona M. Dowling1,2,3, James Phelan4, Julia A. Callender5, Mary Clare Cathcart4, Brian Mehigan6, Paul McCormick6, Tara Dalton3, John C. Coffey7, Alexandra C. Newton5, Jacintha O’Sullivan4, Patrick A. Kiely1,2,3
1Graduate Entry Medical School and Health Research Institute (HRI), University of Limerick, Limerick, Ireland
2Department of Life Sciences, and Materials and Surface Science Institute, University of Limerick, Limerick, Ireland
3Stokes Research Institute, University of Limerick, Limerick, Ireland
4Department of Surgery, Trinity College Dublin, Dublin, Ireland
5Department of Pharmacology, University of California at San Diego, La Jolla, CA, USA
6GEMS, St. James Hospital, Dublin, Ireland
74i Centre for Interventions in Infection, Inflammation and Immunity, Graduate Entry Medical School, University of Limerick, Limerick, Ireland
Patrick A. Kiely, e-mail: [email protected]
Keywords: protein kinase C, IGF-1, cell survival, tumour suppressor, colorectal cancer
Received: October 02, 2015 Accepted: January 31, 2016 Published: March 14, 2016
Despite extensive efforts, cancer therapies directed at the Protein Kinase C (PKC) family of serine/threonine kinases have failed in clinical trials. These therapies have been directed at inhibiting PKC and have, in some cases, worsened disease outcome. Here we examine colon cancer patients and show not only that PKC Beta II is a tumour suppressor, but patients with low levels of this isozyme have significantly decreased disease free survival. Specifically, analysis of gene expression levels of all PKC genes in matched normal and cancer tissue samples from colon cancer patients revealed a striking down-regulation of the gene coding PKC Beta in the cancer tissue (n = 21). Tissue microarray analysis revealed a dramatic down-regulation of PKC Beta II protein levels in both the epithelial and stromal diseased tissue (n = 166). Of clinical significance, low levels of the protein in the normal tissue of patients is associated with a low (10%) 10 year survival compared with a much higher (60%) survival in patients with relatively high levels of the protein. Consistent with PKC Beta II levels protecting against colon cancer, overexpression of PKC Beta II in colon cancer cell lines reveals that PKC Beta II reverses transformation in cell based assays. Further to this, activation of PKC Beta II results in a dramatic downregulation of IGF-I-induced AKT, indicating a role for PKCs in regulating IGF-1 mediated cell survival. Thus, PKC Beta II is a tumour suppressor in colon cancer and low levels serve as a predictor for poor survival outcome.
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