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Molecular Pharmacology

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Research ArticleArticle

Studies on the Mechanism of Resistance to Rapamycin in Human Cancer Cells

Hajime Hosoi, Michael B. Dilling, Linda N. Liu, Mary K. Danks, Takuma Shikata, Aleksander Sekulic, Robert T. Abraham, John C. Lawrence Jr. and Peter J. Houghton
Molecular Pharmacology November 1998, 54 (5) 815-824; DOI: https://doi.org/10.1124/mol.54.5.815
Hajime Hosoi
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Michael B. Dilling
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Linda N. Liu
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Mary K. Danks
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Takuma Shikata
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Aleksander Sekulic
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Robert T. Abraham
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John C. Lawrence Jr.
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Peter J. Houghton
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Abstract

Rapamycin is a potent cytostatic agent that arrests cells in the G1 phase of the cell cycle. The relationships between cellular sensitivity to rapamycin, drug accumulation, expression of mammalian target of rapamycin (mTOR), and inhibition of growth factor activation of ribosomal p70S6 kinase (p70S6k) and dephosphorylation of pH acid stable protein I (eukaryotic initiation factor 4E binding protein) were examined. We show that some cell lines derived from childhood tumors are highly sensitive to growth inhibition by rapamycin, whereas others have high intrinsic resistance (>1000-fold). Accumulation and retention of [14C]rapamycin were similar in sensitive and resistant cells, with all cells examined demonstrating a stable tight binding component. Western analysis showed levels of mTOR were similar in each cell line (<2-fold variation). The activity of p70S6k, activated downstream of mTOR, was similar in four cell lines (range, 11.75–41.8 pmol/2 × 106cells/30 min), but activity was equally inhibited in cells that were highly resistant to rapamycin-induced growth arrest. Rapamycin equally inhibited serum-induced phosphorylation of pH acid stable protein I in Rh1 (intrinsically resistant) and sensitive Rh30 cells. In serum-fasted Rh30 and Rh1 cells, the addition of serum rapidly induced c-MYC (protein) levels. Rapamycin blocked induction in Rh30 cells but not in Rh1 cells. Serum-fasted Rh30/rapa10K cells, selected for high level acquired resistance to rapamycin, showed ≥10-fold increased c-MYC compared with Rh30. These results suggest that the ability of rapamycin to inhibit c-MYC induction correlates with intrinsic sensitivity, whereas failure of rapamycin to inhibit induction or overexpression of c-MYC correlates with intrinsic and acquired resistance, respectively.

Footnotes

    • Received March 16, 1998.
    • Accepted August 10, 1998.
  • Send reprint requests to: Peter J. Houghton, Ph.D., Dept. of Molecular Pharmacology, St. Jude Children’s Research Hospital, 332 N. Lauderdale, Memphis, TN 38105-2794. E-mail:peter.houghton{at}stjude.org

  • ↵1 Current affiliation: Kyoto Prefectural University of Medicine, Kyoto 605, Japan.

  • This work is supported in part by American Cancer Society Grants RPG-95–031-03-DHP (P.J.H.) and RPG-95–040-03 (R.T.A.) and United States Public Health Service Awards CA23099, 5T32CA09346 (L.N.L.), CA21675 (Cancer Center CORE), by a grant from Wyeth-Ayerst, and by American Lebanese, Syrian Associated Charities (ALSAC).

  • The American Society for Pharmacology and Experimental Therapeutics
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Molecular Pharmacology: 54 (5)
Molecular Pharmacology
Vol. 54, Issue 5
1 Nov 1998
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Research ArticleArticle

Studies on the Mechanism of Resistance to Rapamycin in Human Cancer Cells

Hajime Hosoi, Michael B. Dilling, Linda N. Liu, Mary K. Danks, Takuma Shikata, Aleksander Sekulic, Robert T. Abraham, John C. Lawrence and Peter J. Houghton
Molecular Pharmacology November 1, 1998, 54 (5) 815-824; DOI: https://doi.org/10.1124/mol.54.5.815

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Research ArticleArticle

Studies on the Mechanism of Resistance to Rapamycin in Human Cancer Cells

Hajime Hosoi, Michael B. Dilling, Linda N. Liu, Mary K. Danks, Takuma Shikata, Aleksander Sekulic, Robert T. Abraham, John C. Lawrence and Peter J. Houghton
Molecular Pharmacology November 1, 1998, 54 (5) 815-824; DOI: https://doi.org/10.1124/mol.54.5.815
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