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

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 (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.

• Authors: Fumihiko Furuya, Changxue Lu, Mark C Willingham, Sheue-Yann Cheng
• Journal: Carcinogenesis (Carcinogenesis) Vol. 28 Issue 12 Pg. 2451-8 (Dec 2007) ISSN: 1460-2180 [Electronic] England
• PMID: 17660507 (Publication Type: Journal Article, Research Support, N.I.H., Intramural)

Chemical References

• Cdkn1b protein, mouse
• Chromones
• Morpholines
• Phosphoinositide-3 Kinase Inhibitors
• Thyroid Hormone Receptors beta
• Cyclin D1
• Cyclin-Dependent Kinase Inhibitor p27
• 2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one
• Protein Kinases
• MTOR protein, human
• mTOR protein, mouse
• Proto-Oncogene Proteins c-akt
• TOR Serine-Threonine Kinases
• Caspase 3
• Matrix Metalloproteinase 2

Topics

• Adenocarcinoma, Follicular (drug therapy, metabolism, secondary)
• Animals
• Apoptosis
• Caspase 3 (metabolism)
• Cell Movement (drug effects)
• Cell Proliferation (drug effects)
• Chromones (pharmacology, therapeutic use)
• Cyclin D1 (metabolism)
• Cyclin-Dependent Kinase Inhibitor p27 (metabolism)
• Lung Neoplasms (drug therapy, secondary)
• Matrix Metalloproteinase 2 (metabolism)
• Mice
• Mice, Mutant Strains
• Morpholines (pharmacology, therapeutic use)
• Neoplasm Invasiveness
• Phosphoinositide-3 Kinase Inhibitors
• Protein Kinases (metabolism)
• Proto-Oncogene Proteins c-akt (metabolism)
• Signal Transduction
• TOR Serine-Threonine Kinases
• Thyroid Hormone Receptors beta (genetics, metabolism)
• Thyroid Neoplasms (drug therapy, metabolism, pathology)
• Tumor Cells, Cultured