Cucurbitacin E-induced disruption of the actin and vimentin cytoskeleton in prostate carcinoma cells.
Cucurbitacin E has been identified by an empiric screening strategy as a sterol with potent growth inhibitory activity in vitro directed against prostate carcinoma explants (IC50 of 7-50 nM in 2- to 6-day exposures). The mechanism of cucurbitacin cytoxicity has not been elucidated previously. In the present study, we observed that cucurbitacin E caused marked disruption of the actin cytoskeleton, and in a series of cucurbitacin analogues, anti-proliferative activity correlated directly with the disruption of the F-actin cytoskeleton. The distribution of vimentin was also altered in cells exposed to cucurbitacin E, as vimentin associated with drug-induced membrane blebs. The appearance of microtubules was unaffected. Western blot analysis of intracellular actin in cells exposed to cucurbitacins and quantitation of rhodamine-phalloidin binding support the hypothesis that cucurbitacin treatment leads to an inappropriate increase in the filamentous or polymerized actin fraction in prostate carcinoma cells. We conclude that cucurbitacins are potent disruptors of cytoskeletal integrity. Prostate carcinoma cells appear notably sensitive to growth inhibition by cucurbitacin E.
Duncan
K L
KL
Laboratory of Biological Chemistry, National Cancer Institute, NIH, Bethesda, MD, USA.
Duncan
M D
MD
Alley
M C
MC
Sausville
E A
EA
D000199:Actins / Q000378:metabolism; D000970:Antineoplastic Agents / Q000494:pharmacology*; D002451:Cell Compartmentation / Q000187:drug effects; D002455:Cell Division / Q000187:drug effects; D003599:Cytoskeleton / Q000187:drug effects* / Q000378:metabolism*; D004354:Drug Screening Assays, Antitumor; D006801:Humans; D008297:Male; D011471:Prostatic Neoplasms / Q000188:drug therapy* / Q000378:metabolism* / Q000473:pathology; D014315:Triterpenes / Q000494:pharmacology*; D014407:Tumor Cells, Cultured; D014746:Vimentin / Q000378:metabolism
D000199:Actins; D000970:Antineoplastic Agents; D014315:Triterpenes; D014746:Vimentin; C102326:cucurbitacin E