mDia function is critical for the cell suicide program triggered by farnesyl transferase inhibition.
Farnesyl transferase inhibitors (FTIs) exhibit limited cytotoxic effects against human cancer cells, perhaps explaining the limited efficacy of FTIs in clinical trials. Learning how these well-tolerated drugs trigger p53-independent apoptosis in mouse models of cancer might therefore benefit efforts to leverage their utility in clinic. Recent clinical findings indicate that the oncogenic Rho guanine nucleotide exchange factor AKAP13/Lbc is associated with clinical responsiveness, in support of an earlier genetic proof in mice that gain of the geranylgeranylated isoform of RhoB which blocks oncogenic Rho signaling is essential for FTI-induced apoptosis. Here we offer evidence that the RhoB effector mDia is a critical downstream player in this death program. Dominant inhibition of mDia ablated FTI-induced apoptosis but not actin reorganization or growth inhibition, the latter of which has been linked previously to interactions with a RhoB effector kinase pathway that downregulates c-Myc. In nude mice, dominant inhibition of mDia promoted tumor formation and ablated FTI antitumor efficacy. Our findings suggest that the RhoB-mDia pathway is critical for the cell death mechanism engaged by FTI. Further, they suggest that mDia may be important for Rho-dependent survival of oncogenically transformed cells, perhaps driven by AKAP13/Lbc.
Kamasani
Uma
U
Lankenau Institute for Medical Research, Wynnewood, Pennsylvania 19096, USA.
Duhadaway
James B
JB
Alberts
Arthur S
AS
Prendergast
George C
GC
D000818:Animals; D017209:Apoptosis; D002352:Carrier Proteins / Q000378:metabolism*; D016923:Cell Death; D002461:Cell Line, Transformed; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D051231:Farnesyltranstransferase / Q000037:antagonists & inhibitors*; D005347:Fibroblasts / Q000378:metabolism; D000080865:Formins; D015972:Gene Expression Regulation, Neoplastic; D051379:Mice; D008819:Mice, Nude; D008856:Microscopy, Fluorescence; D008954:Models, Biological; D016271:Proto-Oncogene Proteins c-myc / Q000378:metabolism; D020743:rhoB GTP-Binding Protein / Q000378:metabolism