ABSTRACT
Kallikreins are secreted proteases that may play a functional role and/or serve as a serum biomarker for the presence or progression of certain types of cancers. Kallikrein 6 (KLK6, gene; hK6, protein) has been shown to be up-regulated in several types of cancers, including colon. The aims of this study were to elucidate pathways which influence KLK6 gene expression as well as to understand by what cellular mechanism the hK6 protein is secreted in the HCT116 colon cancer cell model system. Our data indicate a central role for caveolin-1 in both KLK6 gene expression and protein secretion. Caveolin-1 (CAV-1), a protein whose expression is frequently altered in colon cancer, can play diverse roles within a cell. It can influence mitogenic signaling pathways as well as affecting protein uptake and secretion. Through the use of isogenic cell model systems wherein CAV-1 or its kinase, SRC, has been altered, we demonstrate that CAV-1 and the presence of caveolae directly enhance hK6 secretion from the cell. Transcriptional regulation may also be altered in colon cancer. We show that in colon cancer cells, CAV-1 can increase the amount of phosphorylated AKT in cells by inhibiting the AKT negative regulators PP1 and PP2A. Although other mitogenic pathways may influence KLK6 expression, it is predominantly through the AKT pathway that CAV-1 influences KLK6 gene expression. This study demonstrates that proteins such as Caveolin-1 and AKT which are known to be altered in colon cancer affect KLK6 expression and hK6 secretion.