Heparin antagonizes cisplatin resistance of A2780 ovarian cancer cells by affecting the Wnt signaling pathway
| Autor: | Fabian Baltes, Gerd Bendas, Martin Schlesinger, Daniel Bastian Pfankuchen, Jin-Ping Li, Tahira Batool |
|---|---|
| Jazyk: | angličtina |
| Rok vydání: | 2017 |
| Předmět: |
0301 basic medicine
cisplatin Pharmacology 03 medical and health sciences Wnt 0302 clinical medicine Downregulation and upregulation Medicine cancer Cytotoxicity Cisplatin Cancer och onkologi tinzaparin business.industry Wnt signaling pathway Cancer chemoresistance Heparin medicine.disease In vitro 030104 developmental biology Oncology 030220 oncology & carcinogenesis Cancer and Oncology business Reprogramming Research Paper medicine.drug |
| Zdroj: | Oncotarget |
| Popis: | // Daniel Bastian Pfankuchen 1 , Fabian Baltes 1 , Tahira Batool 2 , Jin-Ping Li 2 , Martin Schlesinger 1 and Gerd Bendas 1 1 Pharmaceutical Institute, Rheinische Friedrich-Wilhelms-University Bonn, Bonn, Germany 2 Department of Medical Biochemistry and Microbiology, SciLifeLab, University of Uppsala, Uppsala, Sweden Correspondence to: Gerd Bendas, email: gbendas@uni-bonn.de Keywords: tinzaparin, cancer, chemoresistance, Wnt, cisplatin Received: April 14, 2017 Accepted: May 22, 2017 Published: June 28, 2017 ABSTRACT Low molecular weight heparin (LMWH), the guideline based drug for prophylaxis and treatment of cancer-associated thrombosis, was recently shown to sensitize cisplatin resistant A2780cis human ovarian cancer cells for cisplatin cytotoxicity upon 24 h pretreatment with 50 μg × mL -1 of the LMWH tinzaparin in vitro , equivalent to a therapeutic dosage. Thereby, LMWH induced sensitization by transcriptional reprogramming of A2780cis cells via not yet elucidated mechanisms that depend on cellular proteoglycans. Here we aim to illuminate the underlying molecular mechanisms of LMWH in sensitizing A2780cis cells for cisplatin. Using TCF/LEF luciferase promotor assay (Top/Flash) we show that resistant A2780cis cells possess a threefold higher Wnt signaling activity compared to A2780 cells. Furthermore, Wnt pathway blockade by FH535 leads to higher cisplatin sensitivity of A2780cis cells. Glypican-3 (GPC3) is upregulated in A2780cis cells in response to LMWH treatment, probably as counter-regulation to sustain the high Wnt activity against LMWH. Hence, LMWH reduces the cisplatin-induced rise in Wnt activity and TCF-4 expression in A2780cis cells, but keeps sensitive A2780 cells unaffected. Consequently, Wnt signaling pathway appears as primary target of LMWH in sensitizing A2780cis cells for cisplatin toxicity. Considering the outstanding role of LMWH in clinical oncology, this finding appears as promising therapeutic option to hamper chemoresistance. |
| Databáze: | OpenAIRE |
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