title: Transformation-selective apoptotic program triggered by farnesyltransferase inhibitors requires Bin1.
abstract: Neoplastic transformation sensitizes many cells to apoptosis. This phenomenon may underlie the therapeutic benefit of many anticancer drugs, but its molecular basis is poorly understood. We have used a selective and potent farnesyltransferase inhibitor (FTI) to probe a mechanism of apoptosis that is peculiarly linked to neoplastic transformation. While nontoxic to untransformed mouse cells, FTI triggers a massive RhoB-dependent, p53-independent apoptosis in mouse cells that are neoplastically transformed. Here we offer evidence that the BAR adapter-encoding tumor suppressor gene Bin1 is required for this transformation-selective death program. Targeted deletion of Bin1 in primary mouse embyro fibroblasts (MEFs) transformed by E1A+Ras did not affect FTI-induced reversion, actin fiber formation, or growth inhibition, but it abolished FTI-induced apoptosis. The previously defined requirement for RhoB in these effects suggests that Bin1 adapter proteins act downstream or in parallel to RhoB in cell death signaling. The death defect in Bin1 null cells was significant insofar as it abolished FTI efficacy in tumor xenograft assays. p53 deletion did not phenocopy the effects of Bin1 deletion. However, MEFs transformed by SV40 large T antigen+Ras were also resistant to apoptosis by FTI, consistent with other evidence that large T inhibits Bin1-dependent cell death by a p53-independent mechanism. Taken together, the results define a function for Bin1 in apoptosis that is conditional on transformation stress. This study advances understanding of the functions of BAR adapter proteins, which are poorly understood, by revealing genetic interactions with an Rho small GTPase that functions in stress signaling. The frequent losses of Bin1 expression that occur in human breast and prostate cancers may promote tumor progression and limit susceptibility to FTI or other therapeutic agents that exploit the heightened sensitivity of neoplastic cells to apoptosis.
authors.affiliation: Lankenau Institute for Medical Research, Wynnewood, PA 19096, USA.
authors.forename: James B
authors.initials: JB
authors.lastname: DuHadaway
authors.forename: Wei
authors.initials: W
authors.lastname: Du
authors.forename: Scott
authors.initials: S
authors.lastname: Donover
authors.forename: Judith
authors.initials: J
authors.lastname: Baker
authors.forename: Ai-Xue
authors.initials: AX
authors.lastname: Liu
authors.forename: Diane M
authors.initials: DM
authors.lastname: Sharp
authors.forename: Alexander J
authors.initials: AJ
authors.lastname: Muller
authors.forename: George C
authors.initials: GC
authors.lastname: Prendergast
mesh_terms: D000199:Actins / Q000378:metabolism / Q000648:ultrastructure; D048868:Adaptor Proteins, Signal Transducing; D017500:Adenovirus E1A Proteins / Q000235:genetics / Q000378:metabolism; D019883:Alkyl and Aryl Transferases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D000818:Animals; D000952:Antigens, Polyomavirus Transforming / Q000235:genetics / Q000378:metabolism; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology*; D051017:Apoptosis Regulatory Proteins; D002352:Carrier Proteins / Q000187:drug effects / Q000235:genetics / Q000378:metabolism*; D002455:Cell Division / Q000187:drug effects / Q000502:physiology; D002471:Cell Transformation, Neoplastic / Q000235:genetics / Q000378:metabolism*; D002478:Cells, Cultured; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D051231:Farnesyltranstransferase; D005347:Fibroblasts / Q000473:pathology; D017353:Gene Deletion; D008565:Membrane Proteins / Q000378:metabolism; D008715:Methionine / Q000031:analogs & derivatives* / Q000494:pharmacology; D051379:Mice; D016513:Mice, SCID; D009419:Nerve Tissue Proteins; D009687:Nuclear Proteins / Q000187:drug effects / Q000235:genetics / Q000378:metabolism*; D013312:Stress, Physiological; D016159:Tumor Suppressor Protein p53 / Q000235:genetics; D025521:Tumor Suppressor Proteins / Q000187:drug effects / Q000235:genetics / Q000378:metabolism*; D023041:Xenograft Model Antitumor Assays; D018631:ras Proteins / Q000235:genetics / Q000378:metabolism; D020743:rhoB GTP-Binding Protein / Q000235:genetics / Q000378:metabolism
chemical_list: D000199:Actins; D048868:Adaptor Proteins, Signal Transducing; D017500:Adenovirus E1A Proteins; D000952:Antigens, Polyomavirus Transforming; D051017:Apoptosis Regulatory Proteins; C406792:BFAR protein, human; C109221:Bin1 protein, mouse; D002352:Carrier Proteins; D004791:Enzyme Inhibitors; C096898:L 744832; D008565:Membrane Proteins; D009419:Nerve Tissue Proteins; D009687:Nuclear Proteins; D016159:Tumor Suppressor Protein p53; D025521:Tumor Suppressor Proteins; D008715:Methionine; D019883:Alkyl and Aryl Transferases; D051231:Farnesyltranstransferase; D018631:ras Proteins; D020743:rhoB GTP-Binding Protein