| First Author | Furuya F | Year | 2007 |
| Journal | Carcinogenesis | Volume | 28 |
| Issue | 12 | Pages | 2451-8 |
| PubMed ID | 17660507 | Mgi Jnum | J:127728 |
| Mgi Id | MGI:3764751 | Doi | 10.1093/carcin/bgm174 |
| Citation | Furuya F, et al. (2007) Inhibition of phosphatidylinositol 3-kinase delays tumor progression and blocks metastatic spread in a mouse model of thyroid cancer. Carcinogenesis 28(12):2451-8 |
| abstractText | 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 (TRbeta(PV/PV) mice). This TRbeta(PV/PV) mouse harbors a knockin mutant thyroid hormone receptor beta gene (TRbetaPV 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 TRbeta(PV/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)-p70(S6K) signaling, and it decreased cyclin D1 and increased p27(Kip1) 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 TRbeta(PV/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. |
