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.
Highlights
Cucurbitacins are triterpenoid compounds isolated from Cucurbitaceae plants that have been used as folk medicines for centuries
The phosphorylation of vasodilator-stimulated phosphoprotein (VASP) at Ser157, but not Ser239 or Thr278, led to an electrophoretic mobility shift from 46 to 50 kDa in SDSPAGE [23,30]. These results suggest that VASP may be involved in cucurbitacin B (CuB)-induced actin aggregation
We reported here that Ga13/RhoA/protein kinase A (PKA) signaling-mediated VASP phosphorylation plays a critical role in CuB-induced actin aggregation and cofilin-actin rod formation
Summary
Cucurbitacins are triterpenoid compounds isolated from Cucurbitaceae plants that have been used as folk medicines for centuries. They possess a broad spectrum of pharmacological properties including cancer chemoprevention and anticancer activity [1,2,3,4]. Increasing evidence indicates that the actin cytoskeleton may be the common upstream target for cucurbitacins to exert their pharmacological properties, leading to cell deformation, multinucleated cell formation, cell cycle arrest and cell motility inhibition [10,12,13]
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