An inhibitor of mTOR reduces neoplasia and normalizes p70/s6 kinase activity in Pten+/- mice

Katrina Podsypanina; Richard T. Lee; Chris Politis; Ian Hennessy; Allison Crane; Janusz Puc; Mehran Neshat; Hong Wang; Lin Yang; Jay Gibbons; Phil Frost; Valley Dreisbach; John Blenis; Zbigniew Gaciong; Peter Fisher; Charles Sawyers; Lora Hedrick-Ellenson; Ramon Parsons

doi:10.1073/pnas.171060098

An inhibitor of mTOR reduces neoplasia and normalizes p70/s6 kinase activity in Pten^+/- mice

Katrina Podsypanina, Richard T. Lee, Chris Politis, Ian Hennessy, Allison Crane, Janusz Puc, Mehran Neshat, Hong Wang, Lin Yang, Jay Gibbons, Phil Frost, Valley Dreisbach, John Blenis, Zbigniew Gaciong, Peter Fisher, Charles Sawyers, Lora Hedrick-Ellenson, Ramon Parsons

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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.

Original language	English
Pages (from-to)	10320-10325
Number of pages	6
Journal	Proceedings of the National Academy of Sciences of the United States of America
Volume	98
Issue number	18
DOIs	https://doi.org/10.1073/pnas.171060098
State	Published - 28 Aug 2001
Externally published	Yes

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Podsypanina, K., 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. (2001). 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, 98(18), 10320-10325. https://doi.org/10.1073/pnas.171060098

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title = "An inhibitor of mTOR reduces neoplasia and normalizes p70/s6 kinase activity in Pten+/- mice",

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.",

author = "Katrina Podsypanina and Lee, {Richard T.} and Chris Politis and Ian Hennessy and Allison Crane and Janusz Puc and Mehran Neshat and Hong Wang and Lin Yang and Jay Gibbons and Phil Frost and Valley Dreisbach and John Blenis and Zbigniew Gaciong and Peter Fisher and Charles Sawyers and Lora Hedrick-Ellenson and Ramon Parsons",

year = "2001",

month = aug,

day = "28",

doi = "10.1073/pnas.171060098",

language = "English",

volume = "98",

pages = "10320--10325",

journal = "Proceedings of the National Academy of Sciences of the United States of America",

issn = "0027-8424",

publisher = "National Academy of Sciences",

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}

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 2001, '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, pp. 10320-10325. https://doi.org/10.1073/pnas.171060098

TY - JOUR

T1 - An inhibitor of mTOR reduces neoplasia and normalizes p70/s6 kinase activity in Pten+/- mice

AU - Podsypanina, Katrina

AU - Lee, Richard T.

AU - Politis, Chris

AU - Hennessy, Ian

AU - Crane, Allison

AU - Puc, Janusz

AU - Neshat, Mehran

AU - Wang, Hong

AU - Yang, Lin

AU - Gibbons, Jay

AU - Frost, Phil

AU - Dreisbach, Valley

AU - Blenis, John

AU - Gaciong, Zbigniew

AU - Fisher, Peter

AU - Sawyers, Charles

AU - Hedrick-Ellenson, Lora

AU - Parsons, Ramon

PY - 2001/8/28

Y1 - 2001/8/28

N2 - 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.

AB - 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.

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U2 - 10.1073/pnas.171060098

DO - 10.1073/pnas.171060098

M3 - Article

C2 - 11504907

AN - SCOPUS:17944368972

SN - 0027-8424

VL - 98

SP - 10320

EP - 10325

JO - Proceedings of the National Academy of Sciences of the United States of America

JF - Proceedings of the National Academy of Sciences of the United States of America

IS - 18

ER -

An inhibitor of mTOR reduces neoplasia and normalizes p70/s6 kinase activity in Pten+/- mice

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An inhibitor of mTOR reduces neoplasia and normalizes p70/s6 kinase activity in Pten^+/- mice