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PMID: 11504907 Published · ppublish English Journal Article Research Support, Non-U.S. Gov't Research Support, U.S. Gov't, P.H.S.

An inhibitor of mTOR reduces neoplasia and normalizes p70/S6 kinase activity in Pten+/- mice.

Proceedings of the National Academy of Sciences of the United States of America ·Vol. 98 ·No. 18 ·2001-08-28 ·Pages 10320-5

Podsypanina K, Lee RT, Politis C, Hennessy I, Crane A, Puc J, Neshat M, Wang H, Yang L, Gibbons J, Frost P, Dreisbach V, Blenis J, Gaciong Z, Fisher P, Sawyers C, Hedrick-Ellenson L, Parsons R

Abstract

PTEN phosphatase acts as a tumor suppressor by negatively regulating the phosphoinositide 3-kinase (PI3K) signaling pathway. It is unclear which downstream components of this pathway are necessary for oncogenic transformation. In this report we show that transformed cells of PTEN(+/-) mice have elevated levels of phosphorylated Akt and activated p70/S6 kinase associated with an increase in proliferation. Pharmacological inactivation of mTOR/RAFT/FRAP reduced neoplastic proliferation, tumor size, and p70/S6 kinase activity, but did not affect the status of Akt. These data suggest that p70/S6K and possibly other targets of mTOR contribute significantly to tumor development and that inhibition of these proteins may be therapeutic for cancer patients with deranged PI3K signaling.

MeSH Terms
Alleles Animals Base Sequence Cell Transformation, Neoplastic/drug effects DNA Primers/genetics Female Humans Mice Mice, Knockout PTEN Phosphohydrolase Phosphatidylinositol 3-Kinases/metabolism Phosphoric Monoester Hydrolases/deficiency,genetics Protein Kinase Inhibitors Protein Kinases Ribosomal Protein S6 Kinases/metabolism Signal Transduction Sirolimus/analogs & derivatives,pharmacology TOR Serine-Threonine Kinases Tumor Suppressor Proteins Uterine Neoplasms/drug therapy,genetics,metabolism,pathology
Chemicals
DNA Primers Protein Kinase Inhibitors Tumor Suppressor Proteins temsirolimus Protein Kinases MTOR protein, human mTOR protein, mouse Ribosomal Protein S6 Kinases TOR Serine-Threonine Kinases Phosphoric Monoester Hydrolases PTEN Phosphohydrolase PTEN protein, human Sirolimus
Authors & Affiliations
18 authors, click to expand affiliations / ORCID
Podsypanina K
Institute of Cancer Genetics, Department of Pathology and Medicine, College of Physicians and Surgeons, Columbia University, 1150 St. Nicholas Avenue, Russ Berrie Pavilion, New York, NY 10032, USA.
Lee R T
Politis C
Hennessy I
Crane A
Puc J
Neshat M
Wang H
Yang L
Gibbons J
Frost P
Dreisbach V
Blenis J
Gaciong Z
Fisher P
Sawyers C
Hedrick-Ellenson L
Parsons R
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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.171060098
Published
2001-08-28
Epub
2001-00-14
Pages
10320-5
Language
English
Region
United States
NLM ID
7505876
PMCID
PMC56959
Subset
IM
Grants
NCI NIH HHS · CA 75553 · United States
Corrections
CommentIn
PMID: 11526226
External Links
PubMed source DOI: 10.1073/pnas.171060098 PMC Full Text View journal details
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