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Experimental Therapeutics |
Departments of Molecular Pharmacology [H. H., M. B. D., T. S., L. N. L., L. S., G. S. G., P. J. H.] and Experimental Oncology [R. A. A.], St. Jude Children’s Research Hospital, Memphis, Tennessee 38105-2794; and Division of Oncology Research, Mayo Clinic, Rochester, Minnesota 55905 [R. T. A.]
The mammalian target of rapamycin (mTOR) has been shown to link growth factor signaling and posttranscriptional control of translation of proteins that are frequently involved in cell cycle progression. However, the role of this pathway in cell survival has not been demonstrated. Here, we report that rapamycin, a specific inhibitor of mTOR kinase, induces G1 cell cycle arrest and apoptosis in two rhabdomyosarcoma cell lines (Rh1 and Rh30) under conditions of autocrine cell growth. To examine the kinetics of rapamycin action, we next determined the rapamycin sensitivity of rhabdomyosarcoma cells exposed briefly (1 h) or continuously (6 days). Results demonstrate that Rh1 and Rh30 cells were equally sensitive to rapamycin-induced growth arrest and apoptosis under either condition. Apoptosis was detected between 24 and 144 h of exposure to rapamycin. Both cell lines have mutant p53; hence, rapamycin-induced apoptosis appears to be a p53-independent process. To determine whether induction of apoptosis by rapamycin was specifically due to inhibition of mTOR signaling, we engineered Rh1 and Rh30 clones to stably express a mutant form of mTOR that was resistant to rapamycin (Ser2035
Ile; designated mTOR-rr). Rh1 and Rh30 mTOR-rr clones were highly resistant (>3000-fold) to both growth inhibition and apoptosis induced by rapamycin. These results are the first to indicate that rapamycin-induced apoptosis is mediated by inhibition of mTOR. Exogenous insulin-like growth factor (IGF)-I protected both Rh1 and Rh30 from apoptosis, without reactivating ribosomal p70 S6 kinase (p70S6K) downstream of mTOR. However, in rapamycin-treated cultures, the response to IGF-I differed between the cell lines: Rh1 cells proliferated normally, whereas Rh30 cells remained arrested in G1 phase but viable. Rapamycin is known to inhibit synthesis of specific proteins but did not inhibit synthesis or alter the levels of mTOR. To examine the rate at which the mTOR pathway recovered, the ability of IGF-I to stimulate p70S6K activity was followed in cells treated for 1 h with rapamycin and then allowed to recover in medium containing 
100-fold excess of FK506 (to prevent rapamycin from rebinding to its cytosolic receptor FKBP-12). Our results indicate that, in Rh1 cells, rapamycin dissociates relatively slowly from FKBP-12, with a t1/2 of 
17.5 h. in the presence of FK506, whereas there was no recovery of p70S6K activity in the absence of this competitor. This was of interest because rapamycin was relatively unstable under conditions of cell culture having a biological t1/2 of 9.9 h. These results help to explain why cells are sensitive following short exposures to rapamycin and may be useful in guiding the use of rapamycin analogues that are entering clinical trials as novel antitumor agents.
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M. B. Dilling, G. S. Germain, L. Dudkin, A. L. Jayaraman, X. Zhang, F. C. Harwood, and P. J. Houghton 4E-binding Proteins, the Suppressors of Eukaryotic Initiation Factor 4E, Are Down-regulated in Cells with Acquired or Intrinsic Resistance to Rapamycin J. Biol. Chem., April 12, 2002; 277(16): 13907 - 13917. [Abstract] [Full Text] [PDF]
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A. M. Woltman, J. W. de Fijter, S. W. A. Kamerling, S. W. van der Kooij, L. C. Paul, M. R. Daha, and C. van Kooten Rapamycin induces apoptosis in monocyte- and CD34-derived dendritic cells but not in monocytes and macrophages Blood, July 1, 2001; 98(1): 174 - 180. [Abstract] [Full Text] [PDF]
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S. Huang, L. N. Liu, H. Hosoi, M. B. Dilling, T. Shikata, and P. J. Houghton p53/p21CIP1 Cooperate in Enforcing Rapamycin-induced G1 Arrest and Determine the Cellular Response to Rapamycin Cancer Res., April 1, 2001; 61(8): 3373 - 3381. [Abstract] [Full Text]
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H. Harada, J. S. Andersen, M. Mann, N. Terada, and S. J. Korsmeyer p70S6 kinase signals cell survival as well as growth, inactivating the pro-apoptotic molecule BAD PNAS, August 14, 2001; 98(17): 9666 - 9670. [Abstract] [Full Text] [PDF]
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