Home LiteratureArticle Details
PMID: 11504908 Published · ppublish English Journal Article Research Support, Non-U.S. Gov't Research Support, U.S. Gov't, Non-P.H.S. Research Support, U.S. Gov't, P.H.S.

Enhanced sensitivity of PTEN-deficient tumors to inhibition of FRAP/mTOR.

Proceedings of the National Academy of Sciences of the United States of America ·Vol. 98 ·No. 18 ·2001-08-28 ·Pages 10314-9

Neshat MS, Mellinghoff IK, Tran C, Stiles B, Thomas G, Petersen R, Frost P, Gibbons JJ, Wu H, Sawyers CL

Abstract

Recent evidence places the FRAP/mTOR kinase downstream of the phosphatidyl inositol 3-kinase/Akt-signaling pathway, which is up-regulated in multiple cancers because of loss of the PTEN tumor suppressor gene. We performed biological and biochemical studies to determine whether PTEN-deficient cancer cells are sensitive to pharmacologic inhibition of FRAP/mTOR by using the rapamycin derivative CCI-779. In vitro and in vivo studies of isogenic PTEN(+/+) and PTEN(-/-) mouse cells as well as human cancer cells with defined PTEN status showed that the growth of PTEN null cells was blocked preferentially by pharmacologic FRAP/mTOR inhibition. Enhanced tumor growth caused by constitutive activation of Akt in PTEN(+/+) cells also was reversed by CCI-779 treatment, indicating that FRAP/mTOR functions downstream of Akt in tumorigenesis. Loss of PTEN correlated with increased S6 kinase activity and phosphorylation of ribosomal S6 protein, providing evidence for activation of the FRAP/mTOR pathway in these cells. Differential sensitivity to CCI-779 was not explained by differences in biochemical blockade of the FRAP/mTOR pathway, because S6 phosphorylation was inhibited in sensitive and resistant cell lines. These results provide rationale for testing FRAP/mTOR inhibitors in PTEN null human cancers.

MeSH Terms
Adaptor Proteins, Signal Transducing Animals Carrier Proteins/metabolism Cell Cycle Proteins Cells, Cultured Eukaryotic Initiation Factors Humans Immunophilins/antagonists & inhibitors Intracellular Signaling Peptides and Proteins Male Mice Mice, Knockout Mice, Nude Mice, SCID Neoplasms, Experimental/drug therapy,enzymology,genetics PTEN Phosphohydrolase Phosphoproteins/metabolism Phosphoric Monoester Hydrolases/deficiency,genetics Phosphotransferases (Alcohol Group Acceptor) Protein Kinase Inhibitors Protein Kinases Protein Serine-Threonine Kinases Proto-Oncogene Proteins/metabolism Proto-Oncogene Proteins c-akt Rats Ribosomal Protein S6 Kinases/metabolism Sirolimus/analogs & derivatives,pharmacology TOR Serine-Threonine Kinases Tumor Cells, Cultured Tumor Suppressor Proteins
Chemicals
Adaptor Proteins, Signal Transducing Carrier Proteins Cell Cycle Proteins EIF4EBP1 protein, human Eif4ebp1 protein, mouse Eif4ebp1 protein, rat Eukaryotic Initiation Factors Intracellular Signaling Peptides and Proteins Phosphoproteins Protein Kinase Inhibitors Proto-Oncogene Proteins Tumor Suppressor Proteins temsirolimus Protein Kinases Phosphotransferases (Alcohol Group Acceptor) MTOR protein, human mTOR protein, mouse mTOR protein, rat AKT1 protein, human Akt1 protein, rat Protein Serine-Threonine Kinases Proto-Oncogene Proteins c-akt Ribosomal Protein S6 Kinases TOR Serine-Threonine Kinases Phosphoric Monoester Hydrolases PTEN Phosphohydrolase PTEN protein, human Immunophilins Sirolimus
Authors & Affiliations
10 authors, click to expand affiliations / ORCID
Neshat M S
Department of Medicine, University of California School of Medicine, Los Angeles, CA 90095, USA.
Mellinghoff I K
Tran C
Stiles B
Thomas G
Petersen R
Frost P
Gibbons J J
Wu H
Sawyers C L
References (50)
50 references, click to expand
  1. Up-regulation of Akt3 in estrogen receptor-deficient breast cancers and androgen-independent prostate cancer lines.
    J Biol Chem. 1999 Jul 30;274(31):21528-32 PMID: 10419456
  2. Rapamycin blocks the phosphorylation of 4E-BP1 and inhibits cap-dependent initiation of translation.
    EMBO J. 1996 Feb 1;15(3):658-64 PMID: 8599949
  3. Evidence for clonal outgrowth of androgen-independent prostate cancer cells from androgen-dependent tumors through a two-step process.
    Cancer Res. 1999 Oct 1;59(19):5030-6 PMID: 10519419
  4. Drosophila S6 kinase: a regulator of cell size.
    Science. 1999 Sep 24;285(5436):2126-9 PMID: 10497130
  5. PTEN affects cell size, cell proliferation and apoptosis during Drosophila eye development.
    Development. 1999 Dec;126(23):5365-72 PMID: 10556061
  6. Mutational spectra of PTEN/MMAC1 gene: a tumor suppressor with lipid phosphatase activity.
    J Natl Cancer Inst. 1999 Nov 17;91(22):1922-32 PMID: 10564676
  7. Drosophila tumor suppressor PTEN controls cell size and number by antagonizing the Chico/PI3-kinase signaling pathway.
    Genes Dev. 1999 Dec 15;13(24):3244-58 PMID: 10617573
  8. Amplification of AKT2 in human pancreatic cells and inhibition of AKT2 expression and tumorigenicity by antisense RNA.
    Proc Natl Acad Sci U S A. 1996 Apr 16;93(8):3636-41 PMID: 8622988
  9. 4E-BP1 phosphorylation is mediated by the FRAP-p70s6k pathway and is independent of mitogen-activated protein kinase.
    Proc Natl Acad Sci U S A. 1996 Apr 30;93(9):4076-80 PMID: 8633019
  10. A signaling pathway to translational control.
    Cell. 1996 Aug 23;86(4):517-20 PMID: 8752206
  11. Direct inhibition of the signaling functions of the mammalian target of rapamycin by the phosphoinositide 3-kinase inhibitors, wortmannin and LY294002.
    EMBO J. 1996 Oct 1;15(19):5256-67 PMID: 8895571
  12. PTEN, a putative protein tyrosine phosphatase gene mutated in human brain, breast, and prostate cancer.
    Science. 1997 Mar 28;275(5308):1943-7 PMID: 9072974
  13. Identification of a candidate tumour suppressor gene, MMAC1, at chromosome 10q23.3 that is mutated in multiple advanced cancers.
    Nat Genet. 1997 Apr;15(4):356-62 PMID: 9090379
  14. Germline mutations of the PTEN gene in Cowden disease, an inherited breast and thyroid cancer syndrome.
    Nat Genet. 1997 May;16(1):64-7 PMID: 9140396
  15. Germline mutations in PTEN are present in Bannayan-Zonana syndrome.
    Nat Genet. 1997 Aug;16(4):333-4 PMID: 9241266
  16. Growth suppression of glioma cells by PTEN requires a functional phosphatase catalytic domain.
    Proc Natl Acad Sci U S A. 1997 Nov 11;94(23):12479-84 PMID: 9356475
  17. 4E-BP1, a repressor of mRNA translation, is phosphorylated and inactivated by the Akt(PKB) signaling pathway.
    Genes Dev. 1998 Feb 15;12(4):502-13 PMID: 9472019
  18. Targeted disruption of p70(s6k) defines its role in protein synthesis and rapamycin sensitivity.
    Proc Natl Acad Sci U S A. 1998 Apr 28;95(9):5033-8 PMID: 9560223
  19. Inactivation of the tumor suppressor PTEN/MMAC1 in advanced human prostate cancer through loss of expression.
    Proc Natl Acad Sci U S A. 1998 Apr 28;95(9):5246-50 PMID: 9560261
  20. Amino acid sufficiency and mTOR regulate p70 S6 kinase and eIF-4E BP1 through a common effector mechanism.
    J Biol Chem. 1998 Jun 5;273(23):14484-94 PMID: 9603962
  21. Cyclin D expression is controlled post-transcriptionally via a phosphatidylinositol 3-kinase/Akt-dependent pathway.
    J Biol Chem. 1998 Nov 6;273(45):29864-72 PMID: 9792703
  22. Studies on the mechanism of resistance to rapamycin in human cancer cells.
    Mol Pharmacol. 1998 Nov;54(5):815-24 PMID: 9804616
  23. Glycogen synthase kinase-3beta regulates cyclin D1 proteolysis and subcellular localization.
    Genes Dev. 1998 Nov 15;12(22):3499-511 PMID: 9832503
  24. The PTEN/MMAC1 tumor suppressor phosphatase functions as a negative regulator of the phosphoinositide 3-kinase/Akt pathway.
    Proc Natl Acad Sci U S A. 1998 Dec 22;95(26):15587-91 PMID: 9861013
  25. New insights into tumor suppression: PTEN suppresses tumor formation by restraining the phosphoinositide 3-kinase/AKT pathway.
    Proc Natl Acad Sci U S A. 1999 Apr 13;96(8):4240-5 PMID: 10200246
  26. Protein kinase B localization and activation differentially affect S6 kinase 1 activity and eukaryotic translation initiation factor 4E-binding protein 1 phosphorylation.
    Mol Cell Biol. 1999 Jun;19(6):4525-34 PMID: 10330191
  27. PTEN modulates cell cycle progression and cell survival by regulating phosphatidylinositol 3,4,5,-trisphosphate and Akt/protein kinase B signaling pathway.
    Proc Natl Acad Sci U S A. 1999 May 25;96(11):6199-204 PMID: 10339565
  28. Drosophila PTEN regulates cell growth and proliferation through PI3K-dependent and -independent pathways.
    Dev Biol. 2000 May 15;221(2):404-18 PMID: 10790335
  29. PIK3CA as an oncogene in cervical cancer.
    Oncogene. 2000 May 25;19(23):2739-44 PMID: 10851074
  30. A direct linkage between the phosphoinositide 3-kinase-AKT signaling pathway and the mammalian target of rapamycin in mitogen-stimulated and transformed cells.
    Cancer Res. 2000 Jul 1;60(13):3504-13 PMID: 10910062
  31. The Pezcoller lecture: cancer cell cycles revisited.
    Cancer Res. 2000 Jul 15;60(14):3689-95 PMID: 10919634
  32. TOR, a central controller of cell growth.
    Cell. 2000 Oct 13;103(2):253-62 PMID: 11057898
  33. Genetic and biochemical characterization of dTOR, the Drosophila homolog of the target of rapamycin.
    Genes Dev. 2000 Nov 1;14(21):2689-94 PMID: 11069885
  34. Regulation of cellular growth by the Drosophila target of rapamycin dTOR.
    Genes Dev. 2000 Nov 1;14(21):2712-24 PMID: 11069888
  35. Hypoinsulinaemia, glucose intolerance and diminished beta-cell size in S6K1-deficient mice.
    Nature. 2000 Dec 21-28;408(6815):994-7 PMID: 11140689
  36. A role of the kinase mTOR in cellular transformation induced by the oncoproteins P3k and Akt.
    Proc Natl Acad Sci U S A. 2001 Jan 2;98(1):136-41 PMID: 11134523
  37. Regulation of translation initiation by FRAP/mTOR.
    Genes Dev. 2001 Apr 1;15(7):807-26 PMID: 11297505
  38. Chemistry and biology of the immunophilins and their immunosuppressive ligands.
    Science. 1991 Jan 18;251(4991):283-7 PMID: 1702904
  39. Rapamycin selectively inhibits interleukin-2 activation of p70 S6 kinase.
    Nature. 1992 Jul 2;358(6381):70-3 PMID: 1614535
  40. AKT2, a putative oncogene encoding a member of a subfamily of protein-serine/threonine kinases, is amplified in human ovarian carcinomas.
    Proc Natl Acad Sci U S A. 1992 Oct 1;89(19):9267-71 PMID: 1409633
  41. Rapamycin selectively inhibits the growth of childhood rhabdomyosarcoma cells through inhibition of signaling via the type I insulin-like growth factor receptor.
    Cancer Res. 1994 Feb 15;54(4):903-7 PMID: 7508822
  42. Rapamycin selectively represses translation of the "polypyrimidine tract" mRNA family.
    Proc Natl Acad Sci U S A. 1994 May 10;91(10):4441-5 PMID: 8183928
  43. A mammalian protein targeted by G1-arresting rapamycin-receptor complex.
    Nature. 1994 Jun 30;369(6483):756-8 PMID: 8008069
  44. RAFT1: a mammalian protein that binds to FKBP12 in a rapamycin-dependent fashion and is homologous to yeast TORs.
    Cell. 1994 Jul 15;78(1):35-43 PMID: 7518356
  45. Rapamycin selectively inhibits translation of mRNAs encoding elongation factors and ribosomal proteins.
    Proc Natl Acad Sci U S A. 1994 Nov 22;91(24):11477-81 PMID: 7972087
  46. RAPT1, a mammalian homolog of yeast Tor, interacts with the FKBP12/rapamycin complex.
    Proc Natl Acad Sci U S A. 1994 Dec 20;91(26):12574-8 PMID: 7809080
  47. Isolation of a protein target of the FKBP12-rapamycin complex in mammalian cells.
    J Biol Chem. 1995 Jan 13;270(2):815-22 PMID: 7822316
  48. Eukaryotic translation initiation factor 4E regulates expression of cyclin D1 at transcriptional and post-transcriptional levels.
    J Biol Chem. 1995 Sep 8;270(36):21176-80 PMID: 7673150
  49. Control of p70 s6 kinase by kinase activity of FRAP in vivo.
    Nature. 1995 Oct 5;377(6548):441-6 PMID: 7566123
  50. PIK-related kinases: DNA repair, recombination, and cell cycle checkpoints.
    Science. 1995 Oct 6;270(5233):50-1 PMID: 7569949
Article Info
Journal
Proceedings of the National Academy of Sciences of the United States of America
Abbr.
Proc Natl Acad Sci U S A
ISSN
0027-8424
DOI
10.1073/pnas.171076798
Published
2001-08-28
Epub
2001-00-14
Pages
10314-9
Language
English
Region
United States
NLM ID
7505876
PMCID
PMC56958
Subset
IM
Corrections
CommentIn
PMID: 11526226
External Links
PubMed source DOI: 10.1073/pnas.171076798 PMC Full Text View journal details
Analysis Services
Analysis Services

Contact

No. 2 Wenbo Road, Zhangqiu District, Jinan, Shandong

Qilu Normal University · Genelibs Bioinformatics Lab

750 Shunhua Rd, Jinan

2F, Bldg F, University Science Park

Tel: 0531-88819269

WeChat Official Account

Follow our WeChat subscription account for real-time updates and the latest in medical and biological research.


Business Email

E-mail: [email protected]

Copyright © 2026.Genelibs Jinan Honghui Biotechnology Co., Ltd. 鲁ICP备20007159号-2