The zinc finger protein GLI induces cellular sensitivity to the mTOR inhibitor rapamycin

• Published in: Cell growth & differentiation Vol. 10; no. 7; pp. 503 - 516
• Main Authors: LOURO, I. D, MCKIE-BELL, P, GOSNELL, H, BRINDLEY, B. C, BUCY, R. P, RUPPERT, J. M
• Format: Journal Article
• Language: English
• Published: Philadelphia, PA American Association for Cancer Research 01-07-1999
• Subjects: Animals; Antibiotics, Antineoplastic - pharmacology; Biological and medical sciences; Cell Cycle - drug effects; Cell physiology; Cell transformation and carcinogenesis. Action of oncogenes and antioncogenes; Cell Transformation, Neoplastic - metabolism; Cells, Cultured; Clone Cells; Fundamental and applied biological sciences. Psychology; Genes, myc; Genes, ras; Immunosuppressive Agents - pharmacology; Mice; Mice, Nude; Molecular and cellular biology; Neoplasm Transplantation; Oncogene Proteins - metabolism; Phosphotransferases (Alcohol Group Acceptor) - antagonists & inhibitors; Protein Biosynthesis; Protein Kinases; Rhabdomyosarcoma, Alveolar - metabolism; Rhabdomyosarcoma, Embryonal - metabolism; Sirolimus - pharmacology; TOR Serine-Threonine Kinases; Trans-Activators; Transcription Factors - metabolism; Transfection; Transplantation, Heterologous; Zinc Finger Protein GLI1; Zinc Fingers; Cell proliferation; Rat; Sirolimus; Rodentia; Carcinogenesis; Kidney; Antibiotic; Vertebrata; Regulation(control); Sensitivity; Mammalia; Cell line; Protein synthesis; C-Onc gene; Turnover; Chemosensitivity; Inhibition; Transcription factor
• ISSN: 1044-9523; 2377-0732

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.