Warfarin Blocks Gas6-Mediated Axl Activation Required for Pancreatic Cancer Epithelial Plasticity and Metastasis.
Warfarin Blocks Gas6-Mediated Axl Activation Required for Pancreatic Cancer Epithelial Plasticity and Metastasis.
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DOI：
10.1158/0008-5472.can-14-2887-t
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发表时间：
2015-09-15
期刊：
影响因子：
11.2
通讯作者：
Brekken RA
中科院分区：
文献类型：
--
作者：
Kirane A;Ludwig KF;Sorrelle N;Haaland G;Sandal T;Ranaweera R;Toombs JE;Wang M;Dineen SP;Micklem D;Dellinger MT;Lorens JB;Brekken RA
重新利用“旧”药物可以促进快速临床转化，但需要新颖的机制见解。华法林是一种维生素K“拮抗剂”，临床上用于预防血栓形成已有50多年的历史，已被证明具有抗癌作用。我们假设其抗肿瘤活性的分子机制与其对凝血的作用无关，而是由于对肿瘤细胞的 Axl 受体酪氨酸激酶的抑制所致。 Axl 的配体 Gas6（一种维生素 K 依赖性蛋白）的激活在不影响凝血的华法林剂量下受到抑制。在这里，我们表明，用低剂量华法林或其他肿瘤特异性 Axl 靶向剂抑制 Gas6 依赖性 Axl 激活，可以阻止胰腺癌的进展和扩散。华法林还抑制 Axl 依赖性肿瘤细胞迁移、侵袭和增殖，同时增加细胞凋亡和对化疗的敏感性。我们得出的结论是，Gas6 诱导的 Axl 信号传导是胰腺癌进展的关键驱动因素，用低剂量华法林或其他 Axl 靶向药物对其进行抑制可能会改善表达 Axl 的肿瘤患者的预后。
Repurposing ‘old’ drugs can facilitate rapid clinical translation but necessitates novel mechanistic insight. Warfarin, a vitamin K “antagonist” used clinically for the prevention of thrombosis for over 50 years, has been shown to have anti-cancer effects. We hypothesized that the molecular mechanism underlying its anti-tumor activity is unrelated to its effect on coagulation, but is due to inhibition of the Axl receptor tyrosine kinase on tumor cells. Activation of Axl by its ligand Gas6, a vitamin K-dependent protein, is inhibited at doses of warfarin that do not affect coagulation. Here we show that inhibiting Gas6-dependent Axl activation with low dose warfarin or with other tumor-specific Axl targeting agents, blocks the progression and spread of pancreatic cancer. Warfarin also inhibited Axl-dependent tumor cell migration, invasiveness and proliferation while increasing apoptosis and sensitivity to chemotherapy. We conclude that Gas6-induced Axl signaling is a critical driver of pancreatic cancer progression and its inhibition with low dose warfarin or other Axl targeting agents may improve outcome in patients with Axl-expressing tumors.