title: VASP activation via the Gα13/RhoA/PKA pathway mediates cucurbitacin-B-induced actin aggregation and cofilin-actin rod formation.
abstract: Cucurbitacin B (CuB), a potent antineoplastic agent of cucurbitacin triterpenoids, induces rapid disruption of actin cytoskeleton and aberrant cell cycle inhibiting carcinogenesis. However, the underlying molecular mechanism of such anticancer effects remains incompletely understood. In this study, we showed that CuB treatment rapidly induced vasodilator-stimulated phosphoprotein (VASP) phosphorylation (i.e. activation) at the Ser157 residue and generated VASP clumps which were co-localized with amorphous actin aggregates prior to the formation of highly-ordered cofilin-actin rods in melanoma cells. Knockdown of VASP or inhibition of VASP activation using PKA-specific inhibitor H89 suppressed CuB-induced VASP activation, actin aggregation and cofilin-actin rod formation. The VASP activation was mediated by cAMP-independent PKA activation as CuB decreased the levels of cAMP while MDL12330A, an inhibitor of adenylyl cyclase, had weak effect on VASP activation. Knockdown of either Gα13 or RhoA not only suppressed VASP activation, but also ameliorated CuB-induced actin aggregation and abrogated cofilin-actin rod formation. Collectively, our studies highlighted that the CuB-induced actin aggregation and cofilin-actin rod formation was mediated via the Gα13/RhoA/PKA/VASP pathway.
authors.affiliation: Department of Immunobiology, Jinan University, Guangzhou, China.
authors.forename: Yan-Ting
authors.initials: YT
authors.lastname: Zhang
authors.affiliation: Department of Cell Biology, Jinan University, Guangzhou, China.
authors.forename: Li-Hui
authors.initials: LH
authors.lastname: Xu
authors.affiliation: Department of Anatomy and Cell Biology, East Carolina University Brody School of Medicine, Greenville, North Carolina, United States of America.
authors.forename: Qun
authors.initials: Q
authors.lastname: Lu
authors.affiliation: Department of Immunobiology, Jinan University, Guangzhou, China.
authors.forename: Kun-Peng
authors.initials: KP
authors.lastname: Liu
authors.affiliation: Department of Obstetrics and Gynecology, The First Affiliated Hospital of Jinan University, Guangzhou, China.
authors.forename: Pei-Yan
authors.initials: PY
authors.lastname: Liu
authors.affiliation: Guangdong Entomological Institute, Guangzhou, China.
authors.forename: Fang
authors.initials: F
authors.lastname: Ji
authors.affiliation: Southern China Primate Research Center, Guangzhou, China.
authors.forename: Xiao-Ming
authors.initials: XM
authors.lastname: Liu
authors.affiliation: Department of Immunobiology, Jinan University, Guangzhou, China.
authors.forename: Dong-Yun
authors.initials: DY
authors.lastname: Ouyang
authors.affiliation: Department of Immunobiology, Jinan University, Guangzhou, China.
authors.forename: Xian-Hui
authors.initials: XH
authors.lastname: He
mesh_terms: D008841:Actin Cytoskeleton / Q000187:drug effects / Q000378:metabolism; D051339:Actin Depolymerizing Factors / Q000235:genetics / Q000378:metabolism; D000818:Animals; D063646:Carcinogenesis / Q000187:drug effects*; D015815:Cell Adhesion Molecules / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D002453:Cell Cycle / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D017868:Cyclic AMP-Dependent Protein Kinases / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D008546:Melanoma, Experimental / Q000188:drug therapy / Q000235:genetics / Q000473:pathology; D051379:Mice; D008840:Microfilament Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D010750:Phosphoproteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D066329:Protein Aggregates / Q000187:drug effects; D014315:Triterpenes / Q000008:administration & dosage; D020741:rho GTP-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D020742:rhoA GTP-Binding Protein; D000098662:Vasodilator-Stimulated Phosphoprotein
chemical_list: D051339:Actin Depolymerizing Factors; D015815:Cell Adhesion Molecules; D008840:Microfilament Proteins; D010750:Phosphoproteins; D066329:Protein Aggregates; D014315:Triterpenes; D000098662:Vasodilator-Stimulated Phosphoprotein; C041246:cucurbitacin B; D017868:Cyclic AMP-Dependent Protein Kinases; C526380:RhoA protein, mouse; D020741:rho GTP-Binding Proteins; D020742:rhoA GTP-Binding Protein