PI3K/mTOR inhibition can impair tumor invasion and metastasis in vivo despite a lack of antiproliferative action in vitro: implications for targeted therapy.
PI3K/mTOR inhibition can impair tumor invasion and metastasis in vivo despite a lack of antiproliferative action in vitro: implications for targeted therapy.
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DOI：
10.1007/s10549-012-2389-6
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发表时间：
2013-04
影响因子：
3.8
通讯作者：
Slingerland, Joyce M.
中科院分区：
文献类型：
--
作者：
Wander, Seth A.;Zhao, Dekuang;Besser, Alexandra H.;Hong, Feng;Wei, Jianqin;Ince, Tan A.;Milikowski, Clara;Bishopric, Nanette H.;Minn, Andy J.;Creighton, Chad J.;Slingerland, Joyce M.
Oncogenic PI3K/mTOR activation is frequently observed in human cancers and activates cell motility via p27 phosphorylations at T157 and T198. Here we explored the potential for a novel PI3K/mTOR inhibitor to inhibit tumor invasion and metastasis. An MDA-MB-231 breast cancer line variant, MDA-MB-231-1833, with high metastatic bone tropism, was treated with a novel catalytic PI3K/mTOR inhibitor, PF-04691502, at nM doses that did not impair proliferation. Effects on tumor cell motility, invasion, p27 phosphorylation, localization, and bone metastatic outgrowth were assayed. MDA-MB-231-1833 showed increased PI3K/mTOR activation, high levels of cytoplasmic p27pT157pT198 and increased cell motility and invasion in vitro versus parental. PF-04691502 treatment, at a dose that did not affect proliferation, reduced total and cytoplasmic p27, decreased p27pT157pT198 and restored cell motility and invasion to levels seen in MDA-MB-231. p27 knockdown in MDA-MB-231-1833 phenocopied PI3K/mTOR inhibition, whilst overexpression of the phosphomimetic mutant p27T157DT198D caused resistance to the anti-invasive effects of PF-04691502. Pre-treatment of MDA-MB-231-1833 with PF-04691502 significantly impaired metastatic tumor formation in vivo, despite lack of antiproliferative effects in culture and little effect on primary orthotopic tumor growth. A further link between cytoplasmic p27 and metastasis was provided by a study of primary human breast cancers which showed cytoplasmic p27 is associated with increased lymph nodal metastasis and reduced survival. Novel PI3K/mTOR inhibitors may oppose tumor metastasis independent of their growth inhibitory effects, providing a rationale for clinical investigation of PI3K/mTOR inhibitors in settings to prevent micrometastasis. In primary human breast cancers, cytoplasmic p27 is associated with worse outcomes and increased nodal metastasis, and may prove useful as a marker of both PI3K/mTOR activation and PI3K/mTOR inhibitor efficacy. The online version of this article (doi:10.1007/s10549-012-2389-6) contains supplementary material, which is available to authorized users.
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影响因子：
8.8
作者：
Cao, P.;Maira, S-M;Garcia-Echeverria, C.;Hedley, D. W.
通讯作者：
Hedley, D. W.
影响因子：
5.7
作者：
Mallon, Robert;Hollander, Irwin;Gibbons, Jay
通讯作者：
Gibbons, Jay
影响因子：
8.4
作者：
Hashimoto, Isaya;Koizumi, Keiichi;Saiki, Izuo
通讯作者：
Saiki, Izuo
影响因子：
21.3
作者：
Kawauchi, T;Chihama, K;Hoshino, M
通讯作者：
Hoshino, M
影响因子：
82.9
作者：
Liang, J;Zubovitz, J;Slingerland, JM
通讯作者：
Slingerland, JM