The anticancer phytochemical rocaglamide inhibits Rho GTPase activity and cancer cell migration
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Michael S. Becker1, Paul M. Müller2, Jörg Bajorat1, Anne Schroeder1, Marco Giaisi1, Ehsan Amin3, Mohammad R. Ahmadian3, Oliver Rocks2, Rebecca Köhler1, Peter H. Krammer1, Min Li-Weber1
1Tumorimmunology Program (D030), German Cancer Research Center (DKFZ), INF-280, Heidelberg, Germany
2Max Delbrück Center for Molecular Medicine Berlin-Buch, Berlin, Germany
3Institute of Biochemistry and Molecular Biology II, Medical Faculty of The Heinrich-Heine University, Düsseldorf, Germany
Min Li-Weber, email: [email protected]
Keywords: flavaglines, rocaglamide, cell migration, Rho GTPase
Received: October 23, 2015 Accepted: June 04, 2016 Published: June 20, 2016
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.
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