Pfankuchen Daniel Bastian, Baltes Fabian, Batool Tahira, Li Jin-Ping, Schlesinger Martin, Bendas Gerd
Pharmaceutical Institute, Rheinische Friedrich-Wilhelms-University Bonn, Bonn, Germany.
Department of Medical Biochemistry and Microbiology, SciLifeLab, University of Uppsala, Uppsala, Sweden.
Oncotarget. 2017 Jun 28;8(40):67553-67566. doi: 10.18632/oncotarget.18738. eCollection 2017 Sep 15.
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 of the LMWH tinzaparin , 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.
低分子量肝素（LMWH）是预防和治疗癌症相关血栓形成的指南推荐药物，最近有研究表明，用相当于治疗剂量的50μg×mL的LMWH替扎肝素预处理24小时后，可使顺铂耐药的A2780cis人卵巢癌细胞对顺铂的细胞毒性敏感。因此，LMWH通过尚未阐明的依赖细胞蛋白聚糖的机制对A2780cis细胞进行转录重编程，从而诱导敏感性。在此，我们旨在阐明LMWH使A2780cis细胞对顺铂敏感的潜在分子机制。使用TCF/LEF荧光素酶启动子分析（Top/Flash），我们发现耐药的A2780cis细胞的Wnt信号活性比A2780细胞高3倍。此外，FH535阻断Wnt通路可导致A2780cis细胞对顺铂的敏感性更高。硫酸乙酰肝素蛋白聚糖-3（GPC3）在A2780cis细胞中因LMWH处理而上调，可能作为一种反调节来维持针对LMWH的高Wnt活性。因此，LMWH降低了顺铂诱导的A2780cis细胞中Wnt活性和TCF-4表达的升高，但对敏感的A2780细胞没有影响。因此，Wnt信号通路似乎是LMWH使A2780cis细胞对顺铂毒性敏感的主要靶点。考虑到LMWH在临床肿瘤学中的突出作用，这一发现似乎是一种有前景的克服化疗耐药性的治疗选择。
