Salinomycin co-treatment enhances tamoxifen cytotoxicity in luminal A breast tumor cells by facilitating lysosomal degradation of receptor tyrosine kinases
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Ann-Katrin Sommer1,2, Adam Hermawan1, Frauke Martina Mickler3, Bojan Ljepoja1, Pjotr Knyazev2, Christoph Bräuchle3, Axel Ullrich2, Ernst Wagner1, Andreas Roidl1
1Pharmaceutical Biotechnology, Department of Pharmacy, Ludwig-Maximilians-Universität München, 81377 Munich, Germany
2Department of Molecular Biology, Max-Planck-Institute of Biochemistry, 82152 Martinsried, Germany
3Physical Chemistry, Department of Chemistry, Ludwig-Maximilians-Universität München, 81377 Munich, Germany
Andreas Roidl, email: [email protected]
Keywords: tamoxifen, resistance, salinomycin, endosomal trafficking, breast cancer
Received: February 3, 2016 Accepted: June 17, 2016 Published: July 07, 2016
Luminal A breast cancer is the most common breast cancer subtype which is usually treated with selective estrogen receptor modulators (SERMS) like tamoxifen. Nevertheless, one third of estrogen receptor positive breast cancer patients initially do not respond to endocrine therapy and about 40% of luminal A breast tumors recur in five years. In this study, we investigated an alternative treatment approach by combining tamoxifen and salinomycin in luminal A breast cancer cell lines. We have found that salinomycin induces an additional cytotoxic effect by inhibiting the ligand independent activation of ERα. Thereby salinomycin increases the intracellular calcium level. This leads to a premature fusion of endosomes with lysosomes and thus to the degradation of Egfr family members. Since this process is essential for luminal A breast cancer cells to circumvent tamoxifen treatment, the combination of both drugs induces cytotoxicity in tamoxifen sensitive as well as resistant luminal A breast cancer cell lines.
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