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

Kathleen Wantoch Von Rekowski,Piotr Zawierucha,Philipp König,Martin Schlesinger,Svenja Henze,Radosław Januchowski,Gerd Bendas

doi:10.3390/biom9120788

Kathleen Wantoch Von Rekowski, Piotr Zawierucha + Show 5 more

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https://doi.org/10.3390/biom9120788

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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.

Highlights

Chemoresistance, referred to as the loss of tumor sensitivity to the cytotoxic activity of antineoplastic drugs, remains the major restraint in the clinical treatment of cancer patients
Aiming to elucidate the relevance and underlying mechanisms of cell adhesion mediated drug resistance (CAM-DR) in ovarian cancer cells, the present study investigates the role of collagen binding of W1 ovarian cancer cells with respect to cisplatin sensitivity
The cisplatin-resistant subline W1CR displays a significantly reduced sensitivity to cisplatin cytotoxicity, indicated by a roughly eightfold higher EC50 value compared to W1 cells, obtained by MTT assays (Figure 1a, Table S1)

Summary

Introduction

Chemoresistance, referred to as the loss of tumor sensitivity to the cytotoxic activity of antineoplastic drugs, remains the major restraint in the clinical treatment of cancer patients. The molecular resistance mechanisms are versatile, and the functional consequences at the cellular level range from mutations in the signaling pathways to circumvent apoptosis and to trigger proliferation, to changes in the intracellular processing of the drugs, most likely associated with an increased drug efflux by ATP-dependent (ABC)-transporters [1,2]. These clinical considerations are highly relevant for epithelial ovarian cancer, the second most common and the most lethal gynecological malignancy [3]. The ITGB1 knockdown confirms that CAM-DR follows a COL1/ITGB1 signaling axis in W1 cells; a blockade of ILK re-sensitized

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