An inhibitor of mTOR reduces neoplasia and normalizes p70/S6 kinase activity in Pten+/- mice.
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.
Podsypanina
K
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
RT
Politis
C
C
Hennessy
I
I
Crane
A
A
Puc
J
J
Neshat
M
M
Wang
H
H
Yang
L
L
Gibbons
J
J
Frost
P
P
Dreisbach
V
V
Blenis
J
J
Gaciong
Z
Z
Fisher
P
P
Sawyers
C
C
Hedrick-Ellenson
L
L
Parsons
R
R
D000483:Alleles; D000818:Animals; D001483:Base Sequence; D002471:Cell Transformation, Neoplastic / Q000187:drug effects; D017931:DNA Primers / Q000235:genetics; D005260:Female; D006801:Humans; D051379:Mice; D018345:Mice, Knockout; D051059:PTEN Phosphohydrolase; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D010744:Phosphoric Monoester Hydrolases / Q000172:deficiency* / Q000235:genetics; D047428:Protein Kinase Inhibitors; D011494:Protein Kinases; D019893:Ribosomal Protein S6 Kinases / Q000378:metabolism*; D015398:Signal Transduction; D020123:Sirolimus / Q000031:analogs & derivatives / Q000494:pharmacology; D058570:TOR Serine-Threonine Kinases; D025521:Tumor Suppressor Proteins; D014594:Uterine Neoplasms / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism / Q000473:pathology
D017931:DNA Primers; D051059:PTEN Phosphohydrolase; D019869:Phosphatidylinositol 3-Kinases; D010744:Phosphoric Monoester Hydrolases; D047428:Protein Kinase Inhibitors; D011494:Protein Kinases; D019893:Ribosomal Protein S6 Kinases; D020123:Sirolimus; D058570:TOR Serine-Threonine Kinases; D025521:Tumor Suppressor Proteins; C401859:temsirolimus; C546842:MTOR protein, human; C546843:mTOR protein, mouse; C494929:PTEN protein, human