Chemical genetics identifies Rab geranylgeranyl transferase as an apoptotic target of farnesyl transferase inhibitors

Mark R Lackner; Rachel M Kindt; Pamela M Carroll; Katherine Brown; Michael R Cancilla; Changyou Chen; Heshani de Silva; Yvonne Franke; Bo Guan; Tim Heuer; Tak Hung; Kevin Keegan; Jae Moon Lee; Veeraswamy Manne; Carol O'Brien; Dianne Parry; Juan J Perez-Villar; Rajashekar K Reddy; Hong Xiao; Hangjun Zhan; Mark Cockett; Greg Plowman; Kevin Fitzgerald; Michael Costa; Petra Ross-Macdonald

doi:10.1016/j.ccr.2005.03.024

Chemical genetics identifies Rab geranylgeranyl transferase as an apoptotic target of farnesyl transferase inhibitors

Cancer Cell. 2005 Apr;7(4):325-36. doi: 10.1016/j.ccr.2005.03.024.

Affiliation

¹ Exelixis Inc., 170 Harbor Way, South San Francisco, California 94083, USA.

PMID: 15837622
DOI: 10.1016/j.ccr.2005.03.024

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.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Alkyl and Aryl Transferases / antagonists & inhibitors*
Alkyl and Aryl Transferases / metabolism
Alkyl and Aryl Transferases / physiology
Animals
Antineoplastic Agents / pharmacology
Apoptosis / drug effects*
Apoptosis / genetics
Apoptosis / physiology
Caenorhabditis elegans / drug effects
Caenorhabditis elegans / enzymology
Caenorhabditis elegans / genetics
Caenorhabditis elegans Proteins / genetics
Caenorhabditis elegans Proteins / physiology
Calcium-Binding Proteins / genetics
Calcium-Binding Proteins / physiology
Caspases / genetics
Caspases / metabolism
Caspases / physiology
Cell Line, Tumor
Dose-Response Relationship, Drug
Enzyme Inhibitors / pharmacology*
Gene Expression / genetics
Germ Cells / drug effects
Humans
Mutagenesis / genetics
Neoplasms / enzymology
Neoplasms / genetics
Protein Prenylation / drug effects
RNA Interference
RNA, Double-Stranded / genetics
RNA, Small Interfering / genetics
Tumor Suppressor Protein p53 / genetics
Tumor Suppressor Protein p53 / physiology
rab GTP-Binding Proteins / genetics

Substances

Antineoplastic Agents
Caenorhabditis elegans Proteins
Calcium-Binding Proteins
Ced-4 protein, C elegans
Enzyme Inhibitors
RNA, Double-Stranded
RNA, Small Interfering
Tumor Suppressor Protein p53
Alkyl and Aryl Transferases
Rab geranylgeranyltransferase
Caspases
ced-3 protein, C elegans
rab GTP-Binding Proteins