β1-Integrin binding to collagen type 1 transmits breast cancer cells into chemoresistance by activating ABC efflux transporters

Publication date: Available online 25 January 2020Source: Biochimica et Biophysica Acta (BBA) - Molecular Cell ResearchAuthor(s): Fabian Baltes, Vladlena Pfeifer, Katja Silbermann, Julia Caspers, Kathleen Wantoch von Rekowski, Martin Schlesinger, Gerd BendasAbstractMolecular interactions of tumor cells with the microenvironment are regarded as onset of chemotherapy resistance, referred to as cell adhesion mediated drug resistance (CAM-DR). Here we elucidate a mechanism of CAM-DR in breast cancer cells in vitro. We show that human MCF-7 and MDA-MB-231 breast cancer cells decrease their sensitivity towards cisplatin, doxorubicin, and mitoxantrone cytotoxicity upon binding to collagen type 1 (COL1) or fibronectin (FN). The intracellular concentrations of doxorubicin and mitoxantrone were decreased upon cell cultivation on COL1, while cellular cisplatin levels remained unaffected. Since doxorubicin and mitoxantrone are transporter substrates, this refers to ATP binding cassette (ABC) efflux transporter activities. The activation of the transporters BCRP, P-gp and MRP1 was shown by fluorescence assays to distinguish the individual input of these transporters to resistance in presence of COL1 and related to their expression levels by western blot. An ABC transporter inhibitor was able to re-sensitize COL1-treated cells for doxorubicin and mitoxantrone toxicity. Antibody-blocking of β1-integrin (ITGB1) induced sensitization towards the indicated cytostatic drugs by attenuating the ...
Source: Biochimica et Biophysica Acta (BBA) Molecular Cell Research - Category: Molecular Biology Source Type: research