Protein kinase C beta II suppresses colorectal cancer by regulating IGF-1 mediated cell survival.

Catríona M Dowling,Patrick A Kiely,James Phelan,Mary Clare Cathcart,Tara Dalton,Alexandra C Newton,Paul Mccormick,John C Coffey,Brian Mehigan,Jacintha O’Sullivan,Julia A Callender

doi:10.18632/oncotarget.8062

Catríona M Dowling, Patrick A Kiely + Show 9 more

Open Access

https://doi.org/10.18632/oncotarget.8062

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Abstract

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.

Highlights

Following the discovery that the Protein Kinase C (PKC) family members were high affinity intracellular receptors for phorbol-ester tumour promotors, the serine/ threonine kinases were studied intensively in the context of targeting them in cancer [1,2,3,4,5]
The genes encoding protein kinase C isoforms are dysregulated in colon cancer To investigate the change in PKC expression in colon cancer, we used fresh tissue samples that were excised from both the cancer tissue and normal distant tissue of individual patients
Using matched normal and cancer tissue from CRC patients we have shown dysregulation of PKC coding genes in colorectal cancer patients with the most striking difference being a downregulation of PKC Beta II

Summary

Introduction

Following the discovery that the Protein Kinase C (PKC) family members were high affinity intracellular receptors for phorbol-ester tumour promotors, the serine/ threonine kinases were studied intensively in the context of targeting them in cancer [1,2,3,4,5]. The maturation of PKCs into this autoinhibited conformation is dependent on sequential phosphorylation steps at three highly conserved sites termed the activation loop, the turn motif, and the hydrophobic motif [11,12,13] Following these phosphorylation events, the protein is activated by specific secondary messengers that bind to the regulatory domain to mediate the release of the pseudosubstrate segment from the active site [10, 14]. Prolonged activation of PKCs with phorbol esters results in a downregulation of the protein as a result of dephosphorylation and subsequent degradation [16,17,18]

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