The zinc finger protein GLI induces cellular sensitivity to the mTOR inhibitor rapamycin.
The protein synthetic machinery is activated by diverse genetic alterations during tumor progression in vivo and represents an attractive target for cancer therapy. We show that rapamycin inhibits the induction of transformed foci in vitro by GLI, a transcription factor that functions in the sonic hedgehog-patched pathway in tumors. In control cells, which were nontransformed epithelioid RK3E cells and derivative c-MYC- or RAS-transformed sister cell lines, rapamycin inhibits mTOR and mTOR-dependent activities but increases global protein synthesis, perhaps by activating a feedback mechanism. In GLI-transformed cells, rapamycin inhibits global protein synthesis and turnover and prevents cellular proliferation. In contrast to its effects on protein synthesis, rapamycin affects bromodeoxyuridine incorporation and cell cycle occupancy of GLI cells and control cells to a similar extent. Rare, variant GLI cells isolated by selection in rapamycin are also drug-resistant for protein metabolism and for cell cycle progression through G1. Our results indicate that sensitivity to rapamycin can be induced by a specific oncogene and that inhibition of global protein metabolism is linked to the rapamycin-sensitive phenotype.
Louro
I D
ID
Department of Biochemistry and Molecular Genetics, University of Alabama at Birmingham, 35294-3300, USA.
McKie-Bell
P
P
Gosnell
H
H
Brindley
B C
BC
Bucy
R P
RP
Ruppert
J M
JM
D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000494:pharmacology*; D002453:Cell Cycle / Q000187:drug effects; D002471:Cell Transformation, Neoplastic / Q000378:metabolism; D002478:Cells, Cultured; D002999:Clone Cells; D016259:Genes, myc; D011905:Genes, ras; D007166:Immunosuppressive Agents / Q000494:pharmacology*; D051379:Mice; D008819:Mice, Nude; D009368:Neoplasm Transplantation; D015513:Oncogene Proteins / Q000378:metabolism*; D017853:Phosphotransferases (Alcohol Group Acceptor) / Q000037:antagonists & inhibitors*; D014176:Protein Biosynthesis; D011494:Protein Kinases; D018232:Rhabdomyosarcoma, Alveolar / Q000378:metabolism; D018233:Rhabdomyosarcoma, Embryonal / Q000378:metabolism; D020123:Sirolimus / Q000494:pharmacology*; D058570:TOR Serine-Threonine Kinases; D015534:Trans-Activators; D014157:Transcription Factors / Q000378:metabolism*; D014162:Transfection; D014183:Transplantation, Heterologous; D000071676:Zinc Finger Protein GLI1; D016335:Zinc Fingers
D000903:Antibiotics, Antineoplastic; D007166:Immunosuppressive Agents; D015513:Oncogene Proteins; D015534:Trans-Activators; D014157:Transcription Factors; D000071676:Zinc Finger Protein GLI1; D011494:Protein Kinases; D017853:Phosphotransferases (Alcohol Group Acceptor); C546843:mTOR protein, mouse; D058570:TOR Serine-Threonine Kinases; D020123:Sirolimus