Honokiol inhibits c-Met-HO-1 tumor-promoting pathway and its cross-talk with calcineurin inhibitor-mediated renal cancer growth.
Honokiol inhibits c-Met-HO-1 tumor-promoting pathway and its cross-talk with calcineurin inhibitor-mediated renal cancer growth.
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DOI：
10.1038/s41598-017-05455-1
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发表时间：
2017-07-19
影响因子：
4.6
通讯作者：
Pal S
中科院分区：
文献类型：
--
作者：
Balan M;Chakraborty S;Flynn E;Zurakowski D;Pal S
和厚朴酚 (HNK) 是一种小分子，具有有效的抗炎和抗肿瘤特性；然而HNK的分子靶点尚未得到充分研究。受体酪氨酸激酶 c-Met 的过度激活和细胞保护酶血红素加氧酶-1 (HO-1) 的过度表达在肾细胞癌 (RCC) 的生长和进展中发挥着关键作用。有趣的是，钙调神经磷酸酶抑制剂 (CNI) 环孢菌素 A (CsA) 是一种用于预防同种异体移植排斥的免疫抑制剂，也会增加移植患者患 RCC 的风险。我们研究了 c-Met 信号轴对 CNI 诱导的肾肿瘤生长的潜在作用，并测试了 HNK 的抗肿瘤功效。重要的是，CNI 治疗促进了 c-Met 诱导并增强了 c-Met 诱导的 Ras 激活。我们发现 HNK 治疗有效下调肾癌细胞中的 c-Met 磷酸化和 Ras 激活。它抑制 c-Met 和 CNI 诱导的 HO-1 的表达，并促进癌细胞凋亡。在体内，HNK 显着抑制 CNI 诱导的肾肿瘤生长；降低肿瘤组织中磷酸-c-Met和HO-1的表达，降低血管密度。我们的结果表明 HNK 通过抑制 c-Met-Ras-HO-1 轴发挥其抗肿瘤活性的新机制；它对于预防免疫抑制患者的移植后癌症具有显着的治疗潜力。
Honokiol (HNK) is a small molecule with potent anti-inflammatory and anti-tumorigenic properties; yet the molecular targets of HNK are not well studied. Hyperactivation of the receptor tyrosine kinase c-Met and overexpression of the cytoprotective enzyme heme oxygenase-1 (HO-1) play a critical role in the growth and progression of renal cell carcinoma (RCC). Interestingly, the calcineurin inhibitor (CNI) cyclosporine A (CsA), an immunosuppressant used to prevent allograft rejection, can also increase the risk of RCC in transplant patients. We studied the potential role of c-Met signaling axis on CNI-induced renal tumor growth and tested the anti-tumor efficacy of HNK. Importantly, CNI treatment promoted c-Met induction and enhanced c-Met-induced Ras activation. We found that HNK treatment effectively down-regulated both c-Met phosphorylation and Ras activation in renal cancer cells. It inhibited the expression of both c-Met- and CNI-induced HO-1, and promoted cancer cell apoptosis. In vivo, HNK markedly inhibited CNI-induced renal tumor growth; and it decreased the expression of phospho-c-Met and HO-1 and reduced blood vessel density in tumor tissues. Our results suggest a novel mechanism(s) by which HNK exerts its anti-tumor activity through the inhibition of c-Met-Ras-HO-1 axis; and it can have significant therapeutic potential to prevent post-transplantation cancer in immunosuppressed patients.
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