Inhibition of phosphatidylinositol 3-kinase delays tumor progression and blocks metastatic spread in a mouse model of thyroid cancer.
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.
Furuya
Fumihiko
F
Laboratory of Molecular Biology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA.
Lu
Changxue
C
Willingham
Mark C
MC
Cheng
Sheue-Yann
SY
D018263:Adenocarcinoma, Follicular / Q000188:drug therapy* / Q000378:metabolism / Q000556:secondary; D000818:Animals; D017209:Apoptosis; D053148:Caspase 3 / Q000378:metabolism; D002465:Cell Movement / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D002867:Chromones / Q000494:pharmacology / Q000627:therapeutic use*; D019938:Cyclin D1 / Q000378:metabolism; D050760:Cyclin-Dependent Kinase Inhibitor p27 / Q000378:metabolism; D008175:Lung Neoplasms / Q000188:drug therapy / Q000556:secondary; D020778:Matrix Metalloproteinase 2 / Q000378:metabolism; D051379:Mice; D008817:Mice, Mutant Strains; D009025:Morpholines / Q000494:pharmacology / Q000627:therapeutic use*; D009361:Neoplasm Invasiveness; D000081082:Phosphoinositide-3 Kinase Inhibitors; D011494:Protein Kinases / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D015398:Signal Transduction; D058570:TOR Serine-Threonine Kinases; D037042:Thyroid Hormone Receptors beta / Q000235:genetics / Q000378:metabolism*; D013964:Thyroid Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D014407:Tumor Cells, Cultured
C493961:Cdkn1b protein, mouse; D002867:Chromones; D009025:Morpholines; D000081082:Phosphoinositide-3 Kinase Inhibitors; D037042:Thyroid Hormone Receptors beta; D019938:Cyclin D1; D050760:Cyclin-Dependent Kinase Inhibitor p27; C085911:2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one; D011494:Protein Kinases; C546842:MTOR protein, human; C546843:mTOR protein, mouse; D051057:Proto-Oncogene Proteins c-akt; D058570:TOR Serine-Threonine Kinases; D053148:Caspase 3; D020778:Matrix Metalloproteinase 2