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.
Highlights
Malignant tumor diseases induce an upregulation of blood coagulation by a functional interlinkage that has first been described more than 150 years ago, referred to as Trousseau syndrome [1]
Among several other pathways triggering malignancy, which were dependent on heparan sulfate proteoglycan (HSPG), such as FGF-signaling pathway, we explicitly focused our activities on the Wnt signaling pathway, since our gene array data revealed that a tinzaparin treatment of A2780cis cells induces a massive change in signaling activity, and Wnt signaling appears as the most deregulated one
Sensitization of A2780cis cells for cisplatin cytotoxicity by the Low molecular weight heparin (LMWH) tinzaparin was shown to be dependent on an intact HSPG interactome at the cell surface, illustrated by heparitinase susceptibility of resistance and sensitization [17]
Summary
Malignant tumor diseases induce an upregulation of blood coagulation by a functional interlinkage that has first been described more than 150 years ago, referred to as Trousseau syndrome [1]. Antithrombotic prophylaxis is an important component in the therapeutic regimens of cancer patients. According to clinical guidelines for antithrombotic prophylaxis or treatment of patients in oncology, low molecular weight heparin (LMWH) is the drug of choice [2]. There is an ongoing and still controversial discussion whether LMWH can induce more than circumvention of thrombosis in cancer diseases. A retrospective evaluation of clinical data referred to a survival benefit of LMWH treated cancer patients [3], which was confirmed for patient subgroups in a number of prospective clinical trials [4, 5]. Triggered by the glycosaminoglycan (GAG) structure of heparin, LMWHs can interfere at various stages of the metastatic cascade and attenuates tumor cell adhesion, growth factor www.impactjournals.com/oncotarget activity, angiogenesis, enzymatic heparanase activity and thrombin-induced prometastatic signaling [9, 10]
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