Urokinase-type Plasminogen Activator Is a Therapeutic Target for Overcoming Sorafenib Resistance in Hepatoma Cells
Urokinase-type Plasminogen Activator Is a Therapeutic Target for Overcoming Sorafenib Resistance in Hepatoma Cells
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DOI：
10.21873/anticanres.14816
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发表时间：
2021-02
影响因子：
2
通讯作者：
Mami Osawa;Y. Matsuda;Y. Kinoshita;T. Wakai
中科院分区：
文献类型：
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作者：
Mami Osawa;Y. Matsuda;Y. Kinoshita;T. Wakai
背景/目的：索拉非尼是一种多激酶抑制剂，被批准作为肝细胞癌的一线治疗药物。本研究探讨了索拉非尼的耐药机制。材料与方法：将肝癌HepG 2细胞暴露于索拉非尼，并使用细胞增殖/凋亡测定、多重免疫测定、ELISA和蛋白质印迹分析来分析条件培养基的生物活性。尿激酶型纤溶酶原激活剂（uPA）抑制剂或siRNA介导的基因沉默的影响进行了检查，在培养实验和小鼠异种移植肿瘤模型。结果：索拉非尼增加uPA的分泌，这是由Akt抑制剂废除。索拉非尼的生长抑制作用被uPA抑制剂UK 122和阿米洛利显著增强。索拉非尼诱导的细胞凋亡在uPA siRNA转导的细胞中增加2.4倍（p<0.05）。索拉非尼和阿米洛利的联合治疗显著降低了肿瘤体积[平均体积：759 mm 3（索拉非尼）vs. 283 mm 3（索拉非尼加阿米洛利），p<0.05]。结论：uPA可能在索拉非尼耐药中起重要作用。
Background/Aim: Sorafenib is a multikinase inhibitor approved as a first-line therapy for hepatocellular carcinoma. This study examined the sorafenib resistance mechanism. Materials and Methods: Hepatoma HepG2 cells were exposed to sorafenib, and the biological activity of the conditioned media was analyzed using cell proliferation/apoptosis assays, multiplex immunoassays, ELISA, and western blot analyses. The effect of urokinase-type plasminogen activator (uPA) inhibitors or siRNA-mediated gene silencing was examined in culture experiments and a mouse xenograft tumor model. Results: Sorafenib increased uPA secretion, which was abrogated by an Akt inhibitor. The growth-inhibitory effect of sorafenib was significantly enhanced by the uPA inhibitors UK122 and amiloride. Sorafenib-induced apoptosis was increased 2.4-fold in uPA siRNA-transduced cells (p<0.05). Combined therapy with sorafenib and amiloride significantly decreased tumor volumes [mean volume: 759 mm3 (sorafenib) vs. 283 mm3 (sorafenib plus amiloride), p<0.05]. Conclusion: uPA may play a critical role in sorafenib resistance.