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

Autor: Piotr Zawierucha, Martin Schlesinger, Svenja Henze, Radosław Januchowski, Gerd Bendas, Philipp König, Kathleen Wantoch von Rekowski
Rok vydání: 2019
Předmět:
collagen
0301 basic medicine
Integrins
Cell Survival
integrin
cisplatin
Antineoplastic Agents
Protein Serine-Threonine Kinases
Biochemistry
Collagen Type I
Article
03 medical and health sciences
0302 clinical medicine
Cell Line
Tumor
Cell Adhesion
Tumor Microenvironment
medicine
Humans
Cell adhesion
Cytotoxicity
Molecular Biology
Cell Proliferation
Oligonucleotide Array Sequence Analysis
Ovarian Neoplasms
Cisplatin
Gene knockdown
Kinase
Chemistry
Integrin beta1
Multidrug resistance-associated protein 2
chemoresistance
medicine.disease
Gene Expression Regulation
Neoplastic
Gene Ontology
ovarian cancer
030104 developmental biology
Drug Resistance
Neoplasm
Gene Knockdown Techniques
030220 oncology & carcinogenesis
cell adhesion mediated drug resistance (CAM-DR)
Cancer research
Female
Ovarian cancer
Intracellular
Signal Transduction
medicine.drug
Zdroj: Biomolecules
Volume 9
Issue 12
ISSN: 2218-273X
DOI: 10.3390/biom9120788
Popis: 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 &beta
1-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.
Databáze: OpenAIRE
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