Heparin antagonizes cisplatin resistance of A2780 ovarian cancer cells by affecting the Wnt signaling pathway

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.

The Anticoagulant and Nonanticoagulant Properties of Heparin

“…63 Other ways through which heparin is thought to exert anticancer effects are the direct induction of apoptosis of carcinoma cells through cell-cycle arrest 64 and the enhancement of tumor cell sensitivity to chemotherapy by increasing drug uptake and reversing the downregulation of tumor suppressor genes. 65,66 The Wnt signaling pathway is thought to be involved in this latter process. 66 Recently it was also shown that galectin-3, a β-galactoside-binding protein which is commonly overexpressed in most types of cancers, can be inhibited by heparins, independent of their anticoagulant properties.…”

“…65,66 The Wnt signaling pathway is thought to be involved in this latter process. 66 Recently it was also shown that galectin-3, a β-galactoside-binding protein which is commonly overexpressed in most types of cancers, can be inhibited by heparins, independent of their anticoagulant properties. The exact mechanism via which this inhibition results in reduced metastasis is unclear but ligation by heparin has clearly inhibitory effects on galectin-3-mediated cancer cell behavior.…”

Glycosaminoglycans as Tools to Decipher the Platelet Tumor Cell Interaction: A Focus on P-Selectin

“…For heparin, a lot of tumor-associated targets beyond anticoagulation have been identified in the last years. For instance, heparin efficiently blocks enzymes such as heparanase or matrix metalloproteinases, binds growth factors and chemokines, blocks various adhesion receptors, and can sensitize tumor cells for cytotoxic drugs among many other mechanisms [39][40][41]. These effects were reflected in some clinical trials which exhibited an increased survival for heparin treated cancer patients [19,20].…”

H3K4me3 Is a Potential Mediator for Antiproliferative Effects of Calcitriol (1α,25(OH)2D3) in Ovarian Cancer Biology

“…The Wnt pathway plays an important role in the carcinogenesis of all ovarian cancer subtypes including ovarian cancer stem cells (CSCs) [44] and is considered to promote cancer progression as well as chemoresistance between parental A2780 and platinum-resistant A2780cis cell lines [45,46]. Additionally, some findings indicated that epithelial ovarian cancers may derive from a subpopulation of CD44 + CD117 + and that drug-resistant A2780 cells display ovarian CSC properties [47,48].…”