title: The anticancer phytochemical rocaglamide inhibits Rho GTPase activity and cancer cell migration.
abstract: 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.
authors.affiliation: Tumorimmunology Program (D030), German Cancer Research Center (DKFZ), INF-280, Heidelberg, Germany.
authors.forename: Michael S
authors.initials: MS
authors.lastname: Becker
authors.affiliation: Max Delbrück Center for Molecular Medicine Berlin-Buch, Berlin, Germany.
authors.forename: Paul M
authors.initials: PM
authors.lastname: Müller
authors.affiliation: Tumorimmunology Program (D030), German Cancer Research Center (DKFZ), INF-280, Heidelberg, Germany.
authors.forename: Jörg
authors.initials: J
authors.lastname: Bajorat
authors.affiliation: Tumorimmunology Program (D030), German Cancer Research Center (DKFZ), INF-280, Heidelberg, Germany.
authors.forename: Anne
authors.initials: A
authors.lastname: Schroeder
authors.affiliation: Tumorimmunology Program (D030), German Cancer Research Center (DKFZ), INF-280, Heidelberg, Germany.
authors.forename: Marco
authors.initials: M
authors.lastname: Giaisi
authors.affiliation: Institute of Biochemistry and Molecular Biology II, Medical Faculty of The Heinrich-Heine University, Düsseldorf, Germany.
authors.forename: Ehsan
authors.initials: E
authors.lastname: Amin
authors.affiliation: Institute of Biochemistry and Molecular Biology II, Medical Faculty of The Heinrich-Heine University, Düsseldorf, Germany.
authors.forename: Mohammad R
authors.initials: MR
authors.lastname: Ahmadian
authors.affiliation: Max Delbrück Center for Molecular Medicine Berlin-Buch, Berlin, Germany.
authors.forename: Oliver
authors.initials: O
authors.lastname: Rocks
authors.affiliation: Tumorimmunology Program (D030), German Cancer Research Center (DKFZ), INF-280, Heidelberg, Germany.
authors.forename: Rebecca
authors.initials: R
authors.lastname: Köhler
authors.affiliation: Tumorimmunology Program (D030), German Cancer Research Center (DKFZ), INF-280, Heidelberg, Germany.
authors.forename: Peter H
authors.initials: PH
authors.lastname: Krammer
authors.affiliation: Tumorimmunology Program (D030), German Cancer Research Center (DKFZ), INF-280, Heidelberg, Germany.
authors.forename: Min
authors.initials: M
authors.lastname: Li-Weber
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology*; D001572:Benzofurans / Q000494:pharmacology*; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006801:Humans; D020741:rho GTP-Binding Proteins / Q000187:drug effects / Q000378:metabolism*
chemical_list: D000970:Antineoplastic Agents; D001572:Benzofurans; D004791:Enzyme Inhibitors; C107772:rocaglamide; D020741:rho GTP-Binding Proteins
keywords: Rho GTPase; cell migration; flavaglines; rocaglamide