Tumorigenic activity and therapeutic inhibition of Rheb GTPase.
The AKT-mTOR pathway harbors several known and putative oncogenes and tumor suppressors. In a phenotypic screen for lymphomagenesis, we tested candidate genes acting upstream of and downstream from mTOR in vivo. We find that Rheb, a proximal activator of mTORC1, can produce rapid development of aggressive and drug-resistant lymphomas. Rheb causes mTORC1-dependent effects on apoptosis, senescence, and treatment responses that resemble those of Akt. Moreover, Rheb activity toward mTORC1 requires farnesylation and is readily blocked by a pharmacological inhibitor of farnesyltransferase (FTI). In Pten-deficient tumor cells, inhibition of Rheb by FTI is responsible for the drug's anti-tumor effects, such that a farnesylation-independent mutant of Rheb renders these tumors resistant to FTI therapy. Notably, RHEB is highly expressed in some human lymphomas, resulting in mTORC1 activation and increased sensitivity to rapamycin and FTI. Downstream from mTOR, we examined translation initiation factors that have been implicated in transformation in vitro. Of these, only eIF4E was able to enhance lymphomagenesis in vivo. In summary, the Rheb GTPase is an oncogenic activity upstream of mTORC1 and eIF4E and a direct therapeutic target of farnesyltransferase inhibitors in cancer.
Mavrakis
Konstantinos J
KJ
Cancer Biology and Genetics Program, Memorial Sloan-Kettering Cancer Center, New York, NY 10021, USA.
Zhu
Hong
H
Silva
Ricardo L A
RL
Mills
John R
JR
Teruya-Feldstein
Julie
J
Lowe
Scott W
SW
Tam
Wayne
W
Pelletier
Jerry
J
Wendel
Hans-Guido
HG
D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000494:pharmacology; D015153:Blotting, Western; D002471:Cell Transformation, Neoplastic / Q000473:pathology*; D002478:Cells, Cultured; D016922:Cellular Senescence; D004317:Doxorubicin / Q000494:pharmacology; D039561:Eukaryotic Initiation Factor-4E / Q000378:metabolism*; D051231:Farnesyltranstransferase / Q000037:antagonists & inhibitors* / Q000378:metabolism; D005260:Female; D005347:Fibroblasts / Q000166:cytology / Q000378:metabolism; D018628:Gene Dosage; D006801:Humans; D016130:Immunophenotyping; D007166:Immunosuppressive Agents / Q000494:pharmacology; D008223:Lymphoma / Q000378:metabolism / Q000473:pathology*; D000076222:Mechanistic Target of Rapamycin Complex 1; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D020559:Monomeric GTP-Binding Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D046912:Multiprotein Complexes; D009479:Neuropeptides / Q000037:antagonists & inhibitors* / Q000378:metabolism; D051059:PTEN Phosphohydrolase / Q000502:physiology; D010766:Phosphorylation; D010880:Piperidines / Q000494:pharmacology; D011506:Proteins; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D016271:Proto-Oncogene Proteins c-myc / Q000502:physiology; D011725:Pyridines / Q000494:pharmacology; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D000076205:Ras Homolog Enriched in Brain Protein; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction; D020123:Sirolimus / Q000494:pharmacology; D058570:TOR Serine-Threonine Kinases; D014157:Transcription Factors / Q000378:metabolism*; D016159:Tumor Suppressor Protein p53 / Q000502:physiology; D003986:Dibenzocycloheptenes
D000903:Antibiotics, Antineoplastic; D004317:Doxorubicin; D039561:Eukaryotic Initiation Factor-4E; D051231:Farnesyltranstransferase; D007166:Immunosuppressive Agents; D000076222:Mechanistic Target of Rapamycin Complex 1; D020559:Monomeric GTP-Binding Proteins; D046912:Multiprotein Complexes; D009479:Neuropeptides; D051059:PTEN Phosphohydrolase; D010880:Piperidines; D011506:Proteins; D051057:Proto-Oncogene Proteins c-akt; D016271:Proto-Oncogene Proteins c-myc; D011725:Pyridines; D012333:RNA, Messenger; D000076205:Ras Homolog Enriched in Brain Protein; D020123:Sirolimus; D058570:TOR Serine-Threonine Kinases; D014157:Transcription Factors; D016159:Tumor Suppressor Protein p53; C489428:Myc protein, mouse; C490211:RHEB protein, human; C487757:Pten protein, mouse; C115354:lonafarnib; D003986:Dibenzocycloheptenes