Cyclin B1 is a critical target of RhoB in the cell suicide program triggered by farnesyl transferase inhibition.
Farnesyl transferase inhibitors (FTIs) have displayed limited efficacy in clinical trials, possibly because of their relatively limited cytotoxic effects against most human cancer cells. Therefore, efforts to leverage the clinical utility of FTIs may benefit from learning how these agents elicit p53-independent apoptosis in mouse models of cancer. Knockout mouse studies have established that gain of the geranylgeranylated isoform of the small GTPase RhoB is essential for FTI to trigger apoptosis. Here we demonstrate that Cyclin B1 is a crucial target for suppression by RhoB in this death program. Steady-state levels of Cyclin B1 and its associated kinase Cdk1 were suppressed in a RhoB-dependent manner in cells fated to undergo FTI-induced apoptosis. These events were not derivative of cell cycle arrest, because they did not occur in cells fated to undergo FTI-induced growth inhibition. Mechanistic investigations indicated that RhoB mediated transcriptional suppression but also accumulation of Cyclin B1 in the cytosol at early times after FTI treatment, at a time before the subsequent reduction in steady-state protein levels. Enforcing Cyclin B1 expression attenuated apoptosis but not growth inhibition triggered by FTI. Moreover, enforcing Cyclin B1 abolished FTI antitumor activity in graft assays. These findings suggest that Cyclin B1 suppression is a critical step in the mechanism by which FTI triggers apoptosis and robust antitumor efficacy. Our findings suggest that Cyclin B1 suppression may predict favorable clinical responses to FTI, based on cytotoxic susceptibility, and they suggest a rational strategy to address FTI nonresponders by coinhibition of Cdk1 activity.
Kamasani
Uma
U
Lankenau Institute for Medical Research, Wynnewood, Pennsylvania 19096, USA.
Huang
Minzhou
M
Duhadaway
James B
JB
Prochownik
Edward V
EV
Donover
P Scott
PS
Prendergast
George C
GC
D019883:Alkyl and Aryl Transferases / Q000037:antagonists & inhibitors*; D000818:Animals; D017209:Apoptosis; D001483:Base Sequence; D002461:Cell Line, Transformed; D019926:Cyclin B / Q000378:metabolism*; D056744:Cyclin B1; D017931:DNA Primers; D051231:Farnesyltranstransferase; D005455:Fluorescent Antibody Technique; D051379:Mice; D008819:Mice, Nude; D011401:Promoter Regions, Genetic; D020743:rhoB GTP-Binding Protein / Q000378:metabolism*
C534699:CCNB1 protein, human; C534700:Ccnb1 protein, mouse; D019926:Cyclin B; D056744:Cyclin B1; D017931:DNA Primers; D019883:Alkyl and Aryl Transferases; D051231:Farnesyltranstransferase; D020743:rhoB GTP-Binding Protein