title: Chemical genetics identifies Rab geranylgeranyl transferase as an apoptotic target of farnesyl transferase inhibitors.
abstract: A chemical genetics approach identified a cellular target of several proapoptotic farnesyl transferase inhibitors (FTIs). Treatment with these FTIs caused p53-independent apoptosis in Caenorhabditis elegans, which was mimicked by knockdown of endosomal trafficking proteins, including Rab5, Rab7, the HOPS complex, and notably the enzyme Rab geranylgeranyl transferase (RabGGT). These FTIs were found to inhibit mammalian RabGGT with potencies that correlated with their proapoptotic activity. Knockdown of RabGGT induced apoptosis in mammalian cancer cell lines, and both RabGGT subunits were overexpressed in several tumor tissues. These findings validate RabGGT, and by extension endosomal function, as a therapeutically relevant target for modulation of apoptosis, and enhance our understanding of the mechanism of action of FTIs.
authors.affiliation: Exelixis Inc., 170 Harbor Way, South San Francisco, California 94083, USA.
authors.forename: Mark R
authors.initials: MR
authors.lastname: Lackner
authors.forename: Rachel M
authors.initials: RM
authors.lastname: Kindt
authors.forename: Pamela M
authors.initials: PM
authors.lastname: Carroll
authors.forename: Katherine
authors.initials: K
authors.lastname: Brown
authors.forename: Michael R
authors.initials: MR
authors.lastname: Cancilla
authors.forename: Changyou
authors.initials: C
authors.lastname: Chen
authors.forename: Heshani
authors.initials: H
authors.lastname: de Silva
authors.forename: Yvonne
authors.initials: Y
authors.lastname: Franke
authors.forename: Bo
authors.initials: B
authors.lastname: Guan
authors.forename: Tim
authors.initials: T
authors.lastname: Heuer
authors.forename: Tak
authors.initials: T
authors.lastname: Hung
authors.forename: Kevin
authors.initials: K
authors.lastname: Keegan
authors.forename: Jae Moon
authors.initials: JM
authors.lastname: Lee
authors.forename: Veeraswamy
authors.initials: V
authors.lastname: Manne
authors.forename: Carol
authors.initials: C
authors.lastname: O'Brien
authors.forename: Dianne
authors.initials: D
authors.lastname: Parry
authors.forename: Juan J
authors.initials: JJ
authors.lastname: Perez-Villar
authors.forename: Rajashekar K
authors.initials: RK
authors.lastname: Reddy
authors.forename: Hong
authors.initials: H
authors.lastname: Xiao
authors.forename: Hangjun
authors.initials: H
authors.lastname: Zhan
authors.forename: Mark
authors.initials: M
authors.lastname: Cockett
authors.forename: Greg
authors.initials: G
authors.lastname: Plowman
authors.forename: Kevin
authors.initials: K
authors.lastname: Fitzgerald
authors.forename: Michael
authors.initials: M
authors.lastname: Costa
authors.forename: Petra
authors.initials: P
authors.lastname: Ross-Macdonald
mesh_terms: D019883:Alkyl and Aryl Transferases / Q000037:antagonists & inhibitors* / Q000378:metabolism / Q000502:physiology; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects* / Q000235:genetics / Q000502:physiology; D017173:Caenorhabditis elegans / Q000187:drug effects / Q000201:enzymology / Q000235:genetics; D029742:Caenorhabditis elegans Proteins / Q000235:genetics / Q000502:physiology; D002135:Calcium-Binding Proteins / Q000235:genetics / Q000502:physiology; D020169:Caspases / Q000235:genetics / Q000378:metabolism / Q000502:physiology; D045744:Cell Line, Tumor; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D015870:Gene Expression / Q000235:genetics; D005854:Germ Cells / Q000187:drug effects; D006801:Humans; D016296:Mutagenesis / Q000235:genetics; D009369:Neoplasms / Q000201:enzymology / Q000235:genetics; D017368:Protein Prenylation / Q000187:drug effects; D034622:RNA Interference; D012330:RNA, Double-Stranded / Q000235:genetics; D034741:RNA, Small Interfering / Q000235:genetics; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000502:physiology; D020691:rab GTP-Binding Proteins / Q000235:genetics
chemical_list: D000970:Antineoplastic Agents; D029742:Caenorhabditis elegans Proteins; D002135:Calcium-Binding Proteins; C089224:Ced-4 protein, C elegans; D004791:Enzyme Inhibitors; D012330:RNA, Double-Stranded; D034741:RNA, Small Interfering; D016159:Tumor Suppressor Protein p53; D019883:Alkyl and Aryl Transferases; C075607:Rab geranylgeranyltransferase; D020169:Caspases; C089223:ced-3 protein, C elegans; D020691:rab GTP-Binding Proteins