Potential of platinum-resensitization by Wnt signaling modulators as treatment approach for epithelial ovarian cancer
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ORIGINAL ARTICLE – CANCER RESEARCH
Potential of platinum‑resensitization by Wnt signaling modulators as treatment approach for epithelial ovarian cancer Till Kaltofen1 · Valentina Preinfalk1 · Stephanie Schwertler1 · Patricia Fraungruber1 · Helene Heidegger1 · Theresa Vilsmaier1 · Aurelia Vattai1 · Bastian Czogalla1 · Doris Mayr2 · Sven Mahner1 · Udo Jeschke1,3 · Fabian Trillsch1 Received: 21 June 2020 / Accepted: 8 July 2020 © The Author(s) 2020
Abstract Purpose Canonical Wnt/ β-catenin pathway is one mechanism being activated in platinum-resistant epithelial ovarian cancer (EOC). Detecting potential targets for Wnt pathway modulation as a putative future therapeutic approach was the aim of this study. Methods Biological effects of different Wnt modulators (SB216763, XAV939 and triptolide) on the EOC cell lines A2780 and its platinum-resistant clone A2780cis were investigated via multiple functional tests. Immunohistochemistry (IHC) was carried out to compare the expression levels of Wnt marker proteins (β-catenin, snail/ slug, E-cadherin) in patient specimens and to correlate them with lifetime data. Results We could show that activated Wnt signaling of the platinum-resistant EOC cell line A2780cis can be reversed by Wnt manipulators through SB216763 or XAV939. All Wnt manipulators tested consecutively decreased cell proliferation and cell viability. Apoptosis of A2780 and A2780cis was enhanced by triptolide in a dose-dependent manner, whereas cell migration was inhibited by SB216763 and triptolide. IHC analyses elucidated significantly different expression patterns for Wnt markers in the serous subtype. Herein, higher plasmatic snail/ slug expression is associated with improved progressionfree (PFS) and overall survival (OS). Conclusion According to the described effects on EOC biology, all three Wnt manipulators seem to have the potential to augment the impact of a platinum-based chemotherapy in EOC. This is promising as a dominance of this pathway was confirmed in serous histology. Keywords Ovarian cancer · Platinum-resistance · Wnt · β-catenin · Snail/ slug · E-cadherin Abbreviations AEC 3-Amino-9-ethylcarbazole DAB 3,3′-Diaminobenzidine MTT 3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide Electronic supplementary material The online version of this article (https://doi.org/10.1007/s00432-020-03317-4) contains supplementary material, which is available to authorized users. * Till Kaltofen [email protected]‑muenchen.de 1
Department of Obstetrics and Gynecology, University Hospital, LMU Munich, Munich, Germany
2
Department of Pathology, University Hospital, LMU Munich, Munich, Germany
3
Department of Obstetrics and Gynecology, University Hospital Augsburg, Augsburg, Germany
BrdU 5-Bromo-2′-deoxyuridine APC Adenomatous polyposis coli CI Confidence interval DMSO Dimethyl sulfoxide Dsh Dishevelled ELISA Enzyme-linked immunosorbent assay EMT Epithelial-mesenchymal transition EOC Epithelial ovarian cancer FZD Frizzled FIGO International Federation of Gynecolog
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