TY - JOUR
T1 - Protein kinase C beta II suppresses colorectal cancer by regulating IGF-1 mediated cell survival
AU - Dowling, Catríona M.
AU - Phelan, James
AU - Callender, Julia A.
AU - Cathcart, Mary Clare
AU - Mehigan, Brian
AU - McCormick, Paul
AU - Dalton, Tara
AU - Coffey, John C.
AU - Newton, Alexandra C.
AU - O'Sullivan, Jacintha
AU - Kiely, Patrick A.
PY - 2016/4/12
Y1 - 2016/4/12
N2 - 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 IGFI- 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.
AB - 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 IGFI- 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.
KW - Cell survival
KW - Colorectal cancer
KW - IGF-1
KW - Protein kinase C
KW - Tumour suppressor
UR - http://www.scopus.com/inward/record.url?scp=84964713813&partnerID=8YFLogxK
U2 - 10.18632/oncotarget.8062
DO - 10.18632/oncotarget.8062
M3 - Article
C2 - 26989024
AN - SCOPUS:84964713813
SN - 1949-2553
VL - 7
SP - 20919
EP - 20933
JO - Oncotarget
JF - Oncotarget
IS - 15
ER -