Chemical genetics identifies Rab geranylgeranyl transferase as an apoptotic target of farnesyl transferase inhibitors.
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.
Lackner
Mark R
MR
Exelixis Inc., 170 Harbor Way, South San Francisco, California 94083, USA.
Kindt
Rachel M
RM
Carroll
Pamela M
PM
Brown
Katherine
K
Cancilla
Michael R
MR
Chen
Changyou
C
de Silva
Heshani
H
Franke
Yvonne
Y
Guan
Bo
B
Heuer
Tim
T
Hung
Tak
T
Keegan
Kevin
K
Lee
Jae Moon
JM
Manne
Veeraswamy
V
O'Brien
Carol
C
Parry
Dianne
D
Perez-Villar
Juan J
JJ
Reddy
Rajashekar K
RK
Xiao
Hong
H
Zhan
Hangjun
H
Cockett
Mark
M
Plowman
Greg
G
Fitzgerald
Kevin
K
Costa
Michael
M
Ross-Macdonald
Petra
P
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
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