Abstract
Chemotherapeutic drug resistance is a major hurdle in the long-term treatment of cancer. A common chemotherapeutic drug, doxorubicin, used to treat different cancers is facing wide-spread drug resistance. For example, the majority of colon cancer patients develop resistance to doxorubicin treatment. New and effective targeted therapies are required to overcome chemoresistance and decrease the failure rate of chemotherapeutic regimens. The initial aim of this study was to determine the role of a cell surface G protein-coupled receptor, protease-activated receptor 2 (PAR2), in doxorubicin-mediated apoptosis in human colon cancer HT29 cells. PAR2 was shown to be overexpressed in human colon adenocarcinoma tissues versus normal colon tissues. PAR2 activation with a known agonist, 2f-LIGRL-NH2 (2f), attenuated doxorubicin-induced cell death and reactive oxygen species (ROS) production in HT29 cells. PAR2 mediated ERK1/2 phosphorylation was responsible for upregulating anti-apoptotic MCL-1 and Bcl-xL proteins. PAR2 activation also increased levels of phosphorylated p53 upon treatment with doxorubicin, consistent with the anti-apoptotic role of p53. A PAR2 antagonist (AZ3451) or ERK1/2 inhibitor (U0126) was able to restore doxorubicin-mediated cell death, ROS production and p53 phosphorylation levels in HT29 cells. Collectively, this study suggests that PAR2 activation may mediate pro- and anti-apoptotic signalling mechanisms that control resistance to doxorubicin in colon cancer cells.