Biophysical Basis of Drug Resistance in Epithelial Ovarian Cancers

Abstract

Ovarian cancer is one of the most deadly malignancies in women owing to diagnosis at an advanced stage. A major limiting factor in treating late-stage ovarian cancer patients is attributed to chemoresistance against drugs like cisplatin and paclitaxel. Though alterations in physical properties of the tumor microenvironment in a variety of different epithelial cancers, including ovarian cancer, is well appreciated, how such alterations influence normal versus drug-resistant cells remains obscure. In this study, we have compared the behaviour of normal and cisplatin-resistant ovarian cancer cells in response to changes in extracellular matrix (ECM) density. In comparison to control cells, cisplatin-resistant cells were less spread, possessed less number of cell matrix adhesions, and lower degradation potential. Further, cisplatin-resistant cells were found to possess higher baseline contractility compared to normal ovarian cancer cells, as assessed by trypsin de-adhesion assay. However, the enhanced contractility of cisplatin-resistant cells remained insensitive to changes in ECM density. Western blots revealed lower expression levels of the focal adhesion protein vinculin and higher expression levels of the actin crosslinking protein α-actinin in cisplatin-resistant cells compared to control cells. Together, our results point to a potential mesenchymal to amoeboidal transition in ovarian cancer cells that attain drug resistance.Key Words: chemoresistance, tumor microenvironment, extracellular matrix, contractility, focal adhesions, actin bundling proteins.