Inhibition of phosphatidylinositol 3-kinase delays tumor progression and blocks metastatic spread in a mouse model of thyroid cancer

Fumihiko Furuya, Changxue Lu, Mark C. Willingham, Sheue Yann Cheng

Research output: Contribution to journalArticlepeer-review

Abstract

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 (TRβPV/PV mice). This TRβPV/PV mouse harbors a knockin mutant thyroid hormone receptor β gene (TRβPV 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 TRβPV/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 TRβPV/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.

Original languageEnglish (US)
Pages (from-to)2451-2458
Number of pages8
JournalCarcinogenesis
Volume28
Issue number12
DOIs
StatePublished - Dec 2007
Externally publishedYes

ASJC Scopus subject areas

  • Cancer Research

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