The anticancer phytochemical rocaglamide inhibits Rho GTPase activity and cancer cell migration.
The anticancer phytochemical rocaglamide inhibits Rho GTPase activity and cancer cell migration.
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DOI：
10.18632/oncotarget.10188
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发表时间：
2016-08-09
期刊：
影响因子：
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通讯作者：
Li-Weber M
中科院分区：
文献类型：
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作者：
Becker MS;Müller PM;Bajorat J;Schroeder A;Giaisi M;Amin E;Ahmadian MR;Rocks O;Köhler R;Krammer PH;Li-Weber M
化疗是抗癌治疗的支柱之一。尽管化疗药物可使原发肿瘤消退，但许多化疗药物通常会诱导或加速转移形成。此外，转移性肿瘤很大程度上对化疗有抵抗力。由于超过 90% 的癌症患者死于转移而不是原发肿瘤形成，因此需要新的药物来克服这些缺点。在这项研究中，我们发现抗癌植物化学物质 Rocaglamide (Roc-A) 是癌细胞迁移的抑制剂，而癌细胞迁移是转移形成的关键事件。我们发现，Roc-A 在不同类型的人类癌细胞中抑制细胞迁移和侵袭，与其抗增殖和细胞毒性作用无关。从机制上讲，Roc-A 处理会诱导膜突起发生基于 F-肌动蛋白的形态变化。分子机制的进一步研究表明，Roc-A 抑制小 GTP 酶 RhoA、Rac1 和 Cdc42（细胞迁移的主要调节因子）的活性。总而言之，我们的结果提供了证据，表明 Roc-A 可能是抑制转移形成的新型抗癌药物的主要候选药物。
Chemotherapy is one of the pillars of anti-cancer therapy. Although chemotherapeutics cause regression of the primary tumor, many chemotherapeutics are often shown to induce or accelerate metastasis formation. Moreover, metastatic tumors are largely resistant against chemotherapy. As more than 90% of cancer patients die due to metastases and not due to primary tumor formation, novel drugs are needed to overcome these shortcomings. In this study, we identified the anticancer phytochemical Rocaglamide (Roc-A) to be an inhibitor of cancer cell migration, a crucial event in metastasis formation. We show that Roc-A inhibits cellular migration and invasion independently of its anti-proliferative and cytotoxic effects in different types of human cancer cells. Mechanistically, Roc-A treatment induces F-actin-based morphological changes in membrane protrusions. Further investigation of the molecular mechanisms revealed that Roc-A inhibits the activities of the small GTPases RhoA, Rac1 and Cdc42, the master regulators of cellular migration. Taken together, our results provide evidence that Roc-A may be a lead candidate for a new class of anticancer drugs that inhibit metastasis formation.