Carcinogenesis Advance Access published online on July 28, 2007
Carcinogenesis, doi:10.1093/carcin/bgm174
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Published by Oxford University Press 2007.
Inhibition of phosphatidylinositol 3' kinase delays tumor progression and blocks metastatic spread in a mouse model of thyroid cancer
* Laboratory of Molecular Biology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD
Department of Pathology, Wake Forest University, Winston-Salem, NC
To whom correspondence should be addressed at: Building 37, Room 5128, 37 Convent Drive MSC 4264, National Cancer Institute, Bethesda, MD 20892-4264, Tel: (301) 496-4280; Fax: (301) 402-1344; E-mail: chengs{at}mail.nih.gov
Aberrant activation of the phosphatidylinositol 3-kinase (PI3K)-AKT/protein kinase B signaling pathway has been associated with multiple human cancers, including thyroid cancer. Recently we showed that, similar to human thyroid cancer, the PI3K-AKT pathway is overactivated in both the thyroid and metastatic lesions of a mouse model of follicular thyroid carcinoma (TRßPV/PV mice). This TRßPV/PV mouse harbors a knockin mutant thyroid hormone receptor ß gene (TRßPV mutant) that spontaneously develops thyroid cancer and distant metastasis similar to human follicular thyroid cancer. That the activation of the PI3K-AKT signaling contributes to thyroid carcinogenesis raised the possibility that this pathway could be a potential therapeutic target in follicular thyroid carcinoma. The present study tested this possibility by treating TRßPV/PV mice with LY294002 (LY), a potent and specific PI3K inhibitor, and evaluating the effect of LY on the spontaneous development of thyroid cancer. LY treatment inhibited the AKT-mammalian target of rapamycin (mTOR)-p70S6K signaling, and it decreased cyclin D1 and increased p27Kip1 expression to inhibit thyroid tumor growth and reduce tumor cell proliferation. LY treatment increased caspase 3 and decreased phosphorylated BAD to induce apoptosis. In addition, LY treatment reduced the AKT-matrix metalloproteinase 2 signaling to decrease cell motility to block metastatic spread of thyroid tumors. Thus, these altered signaling pathways converged effectively to prolong survival of TRßPV/PV mice treated with LY. No significant adverse effects were observed for wild type mice treated similarly with LY. The present study provides the first preclinical evidence for the in vivo efficacy for LY in the treatment of follicular thyroid cancer.
Key Words: thyroid carcinogenesis • PI3K • AKT • LY294002 • thyroid hormone receptor mutant • mouse model of thyroid cancer
Received April 19, 2007; revised June 30, 2007; accepted July 21, 2007.
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