The Impact of Integrin-Mediated Matrix Adhesion on Cisplatin Resistance of W1 Ovarian Cancer Cells

Abstract

Background: Tumor cell binding to the microenvironment is regarded as the onset of therapeutic resistance, referred to as cell adhesion mediated drug resistance (CAM-DR). Here we elucidate whether CAM-DR occurs in ovarian cancer cells and contributes to still-existing cisplatin resistance. Methods: Cultivation of W1 and cisplatin-resistant W1CR human ovarian cancer cells on collagen-type I (COL1) was followed by whole genome arrays, MTT assays focusing cisplatin cytotoxicity, and AAS detection of intracellular platinum levels. Expression of cisplatin transporters Ctr1 and MRP2 was analyzed. Mechanistic insight was provided by lentiviral β1-integrin (ITGB1) knockdown, or inhibition of integrin-linked kinase (ILK). Results: EC50 values of cisplatin cytotoxicity increased twofold when W1 and W1CR cells were cultivated on COL1, associated with significantly diminished intracellular platinum levels. Transporter deregulation could not be detected at mRNA levels but appears partially responsible at protein levels. The ITGB1 knockdown confirms that CAM-DR follows a COL1/ITGB1 signaling axis in W1 cells; thus, a blockade of ILK re-sensitized W1 cells on COL1 for cisplatin. In contrast, CAM-DR adds to cisplatin resistance in W1CR cells independent of ITGB1. Conclusions: CAM-DR appears relevant for ovarian cancer cells, adding to existing genetic resistance and thus emerges as a target for sensitization strategies.