![[Feedback]](/icons/banner/feedbackACT.gif){kind=icon}
![[For Subscribers]](/icons/banner/subscriberACT.gif){kind=icon}
![[Archive]](/icons/banner/archiveACT.gif){kind=icon}
![[Search]](/icons/banner/searchACT.gif){kind=icon}
![[Contents]](/icons/banner/tocACT.gif){kind=icon}
|
|
|
|
|
||
Vol. 54, Issue 5, 815-824, November 1998
Department of Molecular Pharmacology, St. Jude Children's Research
Hospital, Memphis, Tennessee 38105 (H.H., M.B.D., L.N.L., M.K.D., T.S.,
P.J.H.),
Department of Immunology, Mayo Foundation, Rochester,
Minnesota 55905 (A.S., R.T.A.), and
Department of Pharmacology,
University of Virginia School of Medicine, Charlottesville, Virginia
22908 (J.C.L.)
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 × 106
cells/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.
This article has been cited by other articles:
|
|
 |
|
  T. K. Neklesa and R. W. Davis Superoxide anions regulate TORC1 and its ability to bind Fpr1:rapamycin complex PNAS, September 30, 2008; 105(39): 15166 - 15171. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 K. Hochegger, G. L. Jansky, A. Soleiman, A. M. Wolf, A. Tagwerker, C. Seger, A. Griesmacher, G. Mayer, and A. R. Rosenkranz Differential Effects of Rapamycin in Anti-GBM Glomerulonephritis J. Am. Soc. Nephrol., August 1, 2008; 19(8): 1520 - 1529. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. A. Sanders, A. Lakhani, C. Phornphutkul, K.-Y. Wu, and P. A. Gruppuso The effect of rapamycin on DNA synthesis in multiple tissues from late gestation fetal and postnatal rats Am J Physiol Cell Physiol, August 1, 2008; 295(2): C406 - C413. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 P. A. Gruppuso, S.-W. Tsai, J. M. Boylan, and J. A. Sanders Hepatic translation control in the late-gestation fetal rat Am J Physiol Regulatory Integrative Comp Physiol, August 1, 2008; 295(2): R558 - R567. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 L. H. Wei, H. Su, I. J. Hildebrandt, M. E. Phelps, J. Czernin, and W. A. Weber Changes in Tumor Metabolism as Readout for Mammalian Target of Rapamycin Kinase Inhibition by Rapamycin in Glioblastoma Clin. Cancer Res., June 1, 2008; 14(11): 3416 - 3426. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 F. C. Harwood, L. Shu, and P. J. Houghton mTORC1 Signaling Can Regulate Growth Factor Activation of p44/42 Mitogen-activated Protein Kinases through Protein Phosphatase 2A J. Biol. Chem., February 1, 2008; 283(5): 2575 - 2585. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. J. Ravitz, L. Chen, M. Lynch, and E. V. Schmidt c-myc Repression of TSC2 Contributes to Control of Translation Initiation and Myc-Induced Transformation Cancer Res., December 1, 2007; 67(23): 11209 - 11217. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. Fouladi, F. Laningham, J. Wu, M. A. O'Shaughnessy, K. Molina, A. Broniscer, S. L. Spunt, I. Luckett, C. F. Stewart, P. J. Houghton, et al. Phase I Study of Everolimus in Pediatric Patients With Refractory Solid Tumors J. Clin. Oncol., October 20, 2007; 25(30): 4806 - 4812. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
R. T. Abraham and J. J. Gibbons The Mammalian Target of Rapamycin Signaling Pathway: Twists and Turns in the Road to Cancer Therapy Clin. Cancer Res., June 1, 2007; 13(11): 3109 - 3114. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 K. M. Diehl, E. T. Keller, and K. M. Woods Ignatoski Why should we still care about oncogenes? Mol. Cancer Ther., February 1, 2007; 6(2): 418 - 427. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. S. Lam, A. J. Pantuck, A. S. Belldegrun, and R. A. Figlin Protein Expression Profiles in Renal Cell Carcinoma: Staging, Prognosis, and Patient Selection for Clinical Trials Clin. Cancer Res., January 15, 2007; 13(2): 703s - 708s. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
H. Yan, P. Frost, Y. Shi, B. Hoang, S. Sharma, M. Fisher, J. Gera, and A. Lichtenstein Mechanism by Which Mammalian Target of Rapamycin Inhibitors Sensitize Multiple Myeloma Cells to Dexamethasone-Induced Apoptosis Cancer Res., February 15, 2006; 66(4): 2305 - 2313. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
Y. Shi, H. Yan, P. Frost, J. Gera, and A. Lichtenstein Mammalian target of rapamycin inhibitors activate the AKT kinase in multiple myeloma cells by up-regulating the insulin-like growth factor receptor/insulin receptor substrate-1/phosphatidylinositol 3-kinase cascade Mol. Cancer Ther., October 1, 2005; 4(10): 1533 - 1540. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. Chan, M. E. Scheulen, S. Johnston, K. Mross, F. Cardoso, C. Dittrich, W. Eiermann, D. Hess, R. Morant, V. Semiglazov, et al. Phase II Study of Temsirolimus (CCI-779), a Novel Inhibitor of mTOR, in Heavily Pretreated Patients With Locally Advanced or Metastatic Breast Cancer J. Clin. Oncol., August 10, 2005; 23(23): 5314 - 5322. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. Liu, A. Howes, J. Lesperance, W. B. Stallcup, C. A. Hauser, K. Kadoya, R. G. Oshima, and R. T. Abraham Antitumor Activity of Rapamycin in a Transgenic Mouse Model of ErbB2-Dependent Human Breast Cancer Cancer Res., June 15, 2005; 65(12): 5325 - 5336. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
F. Lefranc, J. Brotchi, and R. Kiss Possible Future Issues in the Treatment of Glioblastomas: Special Emphasis on Cell Migration and the Resistance of Migrating Glioblastoma Cells to Apoptosis J. Clin. Oncol., April 1, 2005; 23(10): 2411 - 2422. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S. Vignot, S. Faivre, D. Aguirre, and E. Raymond mTOR-targeted therapy of cancer with rapamycin derivatives Ann. Onc., April 1, 2005; 16(4): 525 - 537. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 C. Recher, O. Beyne-Rauzy, C. Demur, G. Chicanne, C. Dos Santos, V. M.-D. Mas, D. Benzaquen, G. Laurent, F. Huguet, and B. Payrastre Antileukemic activity of rapamycin in acute myeloid leukemia Blood, March 15, 2005; 105(6): 2527 - 2534. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 K. Inoki, H. Ouyang, Y. Li, and K.-L. Guan Signaling by Target of Rapamycin Proteins in Cell Growth Control Microbiol. Mol. Biol. Rev., March 1, 2005; 69(1): 79 - 100. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
P. Frost, F. Moatamed, B. Hoang, Y. Shi, J. Gera, H. Yan, P. Frost, J. Gibbons, and A. Lichtenstein In vivo antitumor effects of the mTOR inhibitor CCI-779 against human multiple myeloma cells in a xenograft model Blood, December 15, 2004; 104(13): 4181 - 4187. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. P. Dutcher Mammalian Target of Rapamycin Inhibition Clin. Cancer Res., September 15, 2004; 10(18): 6382S - 6387S. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. Huang, L. Shu, J. Easton, F. C. Harwood, G. S. Germain, H. Ichijo, and P. J. Houghton Inhibition of Mammalian Target of Rapamycin Activates Apoptosis Signal-regulating Kinase 1 Signaling by Suppressing Protein Phosphatase 5 Activity J. Biol. Chem., August 27, 2004; 279(35): 36490 - 36496. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
E. K. Rowinsky Curtailing the High Rate of Late-Stage Attrition of Investigational Therapeutics Against Unprecedented Targets in Patients with Lung and Other Malignancies Clin. Cancer Res., June 15, 2004; 10(12): 4220S - 4226S. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
W.-C. Noh, W. H. Mondesire, J. Peng, W. Jian, H. Zhang, J. Dong, G. B. Mills, M.-C. Hung, and F. Meric-Bernstam Determinants of Rapamycin Sensitivity in Breast Cancer Cells Clin. Cancer Res., February 1, 2004; 10(3): 1013 - 1023. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. F. Gera, I. K. Mellinghoff, Y. Shi, M. B. Rettig, C. Tran, J.-h. Hsu, C. L. Sawyers, and A. K. Lichtenstein AKT Activity Determines Sensitivity to Mammalian Target of Rapamycin (mTOR) Inhibitors by Regulating Cyclin D1 and c-myc Expression J. Biol. Chem., January 23, 2004; 279(4): 2737 - 2746. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. M. Slavik, D.-G. Lim, S. J. Burakoff, and D. A. Hafler Rapamycin-resistant Proliferation of CD8+ T Cells Correlates with p27kip1 Down-regulation and bcl-xL Induction, and Is Prevented by an Inhibitor of Phosphoinositide 3-Kinase Activity J. Biol. Chem., January 9, 2004; 279(2): 910 - 919. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 E. K. Rowinsky Signal Events: Cell Signal Transduction and Its Inhibition in Cancer Oncologist, December 1, 2003; 8(90003): 5 - 17. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. P. Tabancay Jr., C.-L. Gau, I. M. P. Machado, E. J. Uhlmann, D. H. Gutmann, L. Guo, and F. Tamanoi Identification of Dominant Negative Mutants of Rheb GTPase and Their Use to Implicate the Involvement of Human Rheb in the Activation of p70S6K J. Biol. Chem., October 10, 2003; 278(41): 39921 - 39930. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. W. Harding Immunophilins, mTOR, and Pharmacodynamic Strategies for a Targeted Cancer Therapy: Commentary re: J. M. Peralba et al., Pharmacodynamic Evaluation of CCI-779, an Inhibitor of mTOR, in Cancer Patients. Clin. Cancer Res., 9: 2887-2892, 2003. Clin. Cancer Res., August 1, 2003; 9(8): 2882 - 2886. [Full Text] [PDF]
|
|
|
|
|
|
E. K. Rowinsky Challenges of Developing Therapeutics That Target Signal Transduction in Patients With Gynecologic and Other Malignancies J. Clin. Oncol., May 15, 2003; 21(90100): 175s - 186. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
K. N. Thimmaiah, J. Easton, S. Huang, K. A. Veverka, G. S. Germain, F. C. Harwood, and P. J. Houghton Insulin-like Growth Factor I-mediated Protection from Rapamycin-induced Apoptosis Is Independent of Ras-Erk1-Erk2 and Phosphatidylinositol 3'-Kinase-Akt Signaling Pathways Cancer Res., January 15, 2003; 63(2): 364 - 374. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. L. Crespo and M. N. Hall Elucidating TOR Signaling and Rapamycin Action: Lessons from Saccharomyces cerevisiae Microbiol. Mol. Biol. Rev., December 1, 2002; 66(4): 579 - 591. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 B. K. Law, A. Chytil, N. Dumont, E. G. Hamilton, M. E. Waltner-Law, M. E. Aakre, C. Covington, and H. L. Moses Rapamycin Potentiates Transforming Growth Factor {beta}-Induced Growth Arrest in Nontransformed, Oncogene-Transformed, and Human Cancer Cells Mol. Cell. Biol., December 1, 2002; 22(23): 8184 - 8198. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. L. McDaniel, C. A. Marshall, K. L. Pappan, and G. Kwon Metabolic and Autocrine Regulation of the Mammalian Target of Rapamycin by Pancreatic {beta}-Cells Diabetes, October 1, 2002; 51(10): 2877 - 2885. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 P. Anand, J. M. Boylan, Y. Ou, and P. A. Gruppuso Insulin signaling during perinatal liver development in the rat Am J Physiol Endocrinol Metab, October 1, 2002; 283(4): E844 - E852. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
Y. Shi, J. Gera, L. Hu, J.-h. Hsu, R. Bookstein, W. Li, and A. Lichtenstein Enhanced Sensitivity of Multiple Myeloma Cells Containing PTEN Mutations to CCI-779 Cancer Res., September 1, 2002; 62(17): 5027 - 5034. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
X. Zhang, L. Shu, H. Hosoi, K. G. Murti, and P. J. Houghton Predominant Nuclear Localization of Mammalian Target of Rapamycin in Normal and Malignant Cells in Culture J. Biol. Chem., July 26, 2002; 277(31): 28127 - 28134. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
Y. Shi, J.-h. Hsu, L. Hu, J. Gera, and A. Lichtenstein Signal Pathways Involved in Activation of p70S6K and Phosphorylation of 4E-BP1 following Exposure of Multiple Myeloma Tumor Cells to Interleukin-6 J. Biol. Chem., May 3, 2002; 277(18): 15712 - 15720. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
L. Shu, X. Zhang, and P. J. Houghton Myogenic Differentiation Is Dependent on Both the Kinase Function and the N-terminal Sequence of Mammalian Target of Rapamycin J. Biol. Chem., May 3, 2002; 277(19): 16726 - 16732. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
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]
|
|
|
|
|
|
M. S. Neshat, I. K. Mellinghoff, C. Tran, B. Stiles, G. Thomas, R. Petersen, P. Frost, J. J. Gibbons, H. Wu, and C. L. Sawyers Enhanced sensitivity of PTEN-deficient tumors to inhibition of FRAP/mTOR PNAS, August 10, 2001; (2001) 171076798. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
K. Podsypanina, R. T. Lee, C. Politis, I. Hennessy, A. Crane, J. Puc, M. Neshat, H. Wang, L. Yang, J. Gibbons, et al. An inhibitor of mTOR reduces neoplasia and normalizes p70/S6 kinase activity in Pten+/- mice PNAS, August 10, 2001; (2001) 171060098. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
L. Dudkin, M. B. Dilling, P. J. Cheshire, F. C. Harwood, M. Hollingshead, S. G. Arbuck, R. Travis, E. A. Sausville, and P. J. Houghton Biochemical Correlates of mTOR Inhibition by the Rapamycin Ester CCI-779 and Tumor Growth Inhibition Clin. Cancer Res., June 1, 2001; 7(6): 1758 - 1764. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
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]
|
|
|
|
 |
|
 J. M. Slavik, D.-G. Lim, S. J. Burakoff, and D. A. Hafler Uncoupling p70s6 Kinase Activation and Proliferation: Rapamycin-Resistant Proliferation of Human CD8+ T Lymphocytes J. Immunol., March 1, 2001; 166(5): 3201 - 3209. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
B. Geoerger, K. Kerr, C.-B. Tang, K.-M. Fung, B. Powell, L. N. Sutton, P. C. Phillips, and A. J. Janss Antitumor Activity of the Rapamycin Analog CCI-779 in Human Primitive Neuroectodermal Tumor/Medulloblastoma Models as Single Agent and in Combination Chemotherapy Cancer Res., February 1, 2001; 61(4): 1527 - 1532. [Abstract] [Full Text]
|
|
|
|
|
|
M. Aoki, E. Blazek, and P. K. Vogt A role of the kinase mTOR in cellular transformation induced by the oncoproteins P3k and Akt PNAS, December 22, 2000; (2000) 11528498. [Abstract] [Full Text]
|
|
|
|
|
|
A. Misawa, H. Hosoi, A. Arimoto, T. Shikata, S. Akioka, T. Matsumura, P. J. Houghton, and T. Sawada N-Myc Induction Stimulated by Insulin-like Growth Factor I through Mitogen-activated Protein Kinase Signaling Pathway in Human Neuroblastoma Cells Cancer Res., January 1, 2000; 60(1): 64 - 69. [Abstract] [Full Text]
|
|
|
|
 |
|
 I. D. Louro, P. McKie-Bell, H. Gosnell, B. C. Brindley, R. P. Bucy, and J. M. Ruppert The Zinc Finger Protein GLI Induces Cellular Sensitivity to the mTOR Inhibitor Rapamycin Cell Growth Differ., July 1, 1999; 10(7): 503 - 516. [Abstract] [Full Text]
|
|
|
|
|
|
H. Hosoi, M. B. Dilling, T. Shikata, L. N. Liu, L. Shu, R. A. Ashmun, G. S. Germain, R. T. Abraham, and P. J. Houghton Rapamycin Causes Poorly Reversible Inhibition of mTOR and Induces p53-independent Apoptosis in Human Rhabdomyosarcoma Cells Cancer Res., February 1, 1999; 59(4): 886 - 894. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. M. Boylan, P. Anand, and P. A. Gruppuso Ribosomal Protein S6 Phosphorylation and Function during Late Gestation Liver Development in the Rat J. Biol. Chem., November 21, 2001; 276(48): 44457 - 44463. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. Aoki, E. Blazek, and P. K. Vogt A role of the kinase mTOR in cellular transformation induced by the oncoproteins P3k and Akt PNAS, January 2, 2001; 98(1): 136 - 141. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
K. Podsypanina, R. T. Lee, C. Politis, I. Hennessy, A. Crane, J. Puc, M. Neshat, H. Wang, L. Yang, J. Gibbons, et al. An inhibitor of mTOR reduces neoplasia and normalizes p70/S6 kinase activity in Pten+/- mice PNAS, August 28, 2001; 98(18): 10320 - 10325. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. S. Neshat, I. K. Mellinghoff, C. Tran, B. Stiles, G. Thomas, R. Petersen, P. Frost, J. J. Gibbons, H. Wu, and C. L. Sawyers Enhanced sensitivity of PTEN-deficient tumors to inhibition of FRAP/mTOR PNAS, August 28, 2001; 98(18): 10314 - 10319. [Abstract] [Full Text] [PDF]
|
|
 |
 |
 |
|
 |
 |
 |
