Evaluation of FAK and MDR1 Crosstalk in Platinum Resistant Ovarian Cancer Cells

Evaluation of FAK and MDR1 Crosstalk in Platinum Resistant Ovarian Cancer Cells

Platinum resistance continues to be a major challenge in the chemotherapeutic management of ovarian cancer. Increased phosphorylation of a tyrosine kinase, Focal Adhesion Kinase (FAK) has been implicated in the development of this platinum resistance. A multidrug resistant gene (MDR1) codes for the P-glycoprotein, a protein that plays an important role in the chemotherapeutic resistance of the platinum resistant ovarian cancer cells. Therefore, it was suspected that there may be an intracellular link between FAK and MDR1 that can determine the drug resistance and consequent escape from the cytotoxicity of the drugs in ovarian cancer cells. Hence, it is hypothesized that FAK plays an important role in activating the MDR1, that can lead to platinum resistance in a sub-set of ovarian cancer cells. To verify our hypothesis, the platinum resistant cells were treated with varying concentrations of Y15, and the DNA fragmentation and poly ADP ribose polymerase (PARP) cleavage assays were performed to determine the extent of cell death. Western blot analysis for the phosphorylated FAK and P-glycoprotein were also utilized to evaluate the levels of phosphorylation and protein expression respectively, in response to Y15 treatment. The results of our study provides great insight in confirming a potentially new targeted approach to treat recurrent ovarian cancer, as it is the first to link the FAK dependent cytotoxic mechanism of Y15 to the MDR1 gene in platinum resistant ovarian cancer cells. I would like to thank the Royal Dames for providing the financial support to conduct this research.