Salidroside ameliorated hypoxia-induced tumorigenesis of BxPC-3 cells via downregulating hypoxia-inducible factor (HIF)-1α and LOXL2
Salidroside ameliorated hypoxia-induced tumorigenesis of BxPC-3 cells via downregulating hypoxia-inducible factor (HIF)-1α and LOXL2
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DOI：
10.1002/jcb.29000
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发表时间：
2020-01-01
影响因子：
4
通讯作者：
Pu, Yumei
中科院分区：
文献类型：
--
作者：
Chen, Xiaoping;Kou, Yubin;Pu, Yumei
在此，我们发现红景天苷抑制常氧和缺氧条件下培养的人胰腺癌 BxPC-3 细胞中的缺氧诱导因子 1 α (HIF-1 α) 和赖氨酰氧化酶样蛋白 2 (LOXL2)。为了研究红景天苷对 BxPC-3 细胞肿瘤发生的影响以及 HIF-1 α 和 LXCL2 是否参与该过程，在缺氧条件下用 50 μg/mL 红景天苷或 50 μM KC7F2（一种 HIF-1 α 抑制剂）处理转染或不转染 LOXL2 过表达载体的细胞。分别使用 CCK-8 和 Transwell 小室测定评估细胞活力和侵袭。通过蛋白质印迹分析测定 E-钙粘蛋白和基质金属蛋白酶 2/9 (MMP 2/9) 的表达，以评估分子水平的细胞流动性。我们证实缺氧会增加 LOXL2 并诱导 BxPC-3 细胞的肿瘤发生，促进细胞增殖和侵袭，增强 MMP2/9，同时减少 E-cadherin。有趣的是，红景天苷和 KC7F2 均显着延缓缺氧诱导的癌发生，但 LOXL2 过表达则增强这一作用。此外，红景天苷和KC7F2可降低LOXL2，并逆转LOXL2过表达诱导的BxPC-3细胞的肿瘤发生。鉴于红景天苷对HIF-1α表达的抑制作用，我们的数据表明：（1）LOXL2是红景天苷和KC7F2对BxPC-3细胞的癌症进展显示抑制作用的机制； (2) 红景天苷很可能通过 HIF-1 α/LOXL2 途径发挥其抗癌作用。总之，红景天苷是一种新型的胰腺癌治疗药物，其潜在机制是下调HIF-1α和LXCL2。
Herein, we found that salidroside suppressed hypoxia-inducible factor 1 alpha (HIF-1 alpha) and lysyl oxidase-like protein 2 (LOXL2) within human pancreatic cancer BxPC-3 cells cultured both under normoxia and hypoxia condition. To investigate the effect of salidroside on tumorigenesis of BxPC-3 cells and whether HIF-1 alpha and LXCL2 were involved in this process, cells transfected with or without LOXL2 overexpression vector, were treated with 50 mu g/mL of salidroside or 50 mu M of KC7F2 (a HIF-1 alpha inhibitor) under hypoxia. Cell viability and invasion were assessed using CCK-8 and Transwell chamber assay, respectively. Expression of E-cadherin and matrix metalloproteinase 2/9 (MMP 2/9) was determined, by Western blot analysis, to assess cell mobility at molecular levels. We confirmed that hypoxia increased LOXL2 and induced tumorigenesis of BxPC-3 cells, as evidenced by promoted cell proliferation and invasion, enhanced MMP2/9 while reduced E-cadherin. Interestingly, hypoxia-induced carcinogenesis was significantly retarded by both salidroside and KC7F2, however, enhanced with LOXL2 overexpression. Besides, salidroside and KC7F2 reduced LOXL2, and reversed the tumorigenesis of BxPC-3 cells induced by LOXL2 overexpression. Given the inhibitory effect of salidroside on HIF-1 alpha expression, our data suggested that: (1) LOXL2 was the mechanism, whereby salidroside and KC7F2 showed inhibitory effect on cancer progression of BxPC-3 cells; (2) salidroside exerted its anticancer effect, most likely, by a HIF-1 alpha/LOXL2 pathway. In conclusion, salidroside was a novel therapeutic drug in pancreatic cancer, and downregulation of HIF-1 alpha and LXCL2 was the underlying mechanism.