Effects of metformin and pioglitazone combination on apoptosis and AMPK/mTOR signaling pathway in human anaplastic thyroid cancer cells
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Date
2020
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Abstract
Anaplastic cancer constitutes 1% of thyroid cancers, and it is one of the most aggressive cancers. Treatment options are external radiation therapy and/or chemotherapy. The success rate with these treatment modalities is not satisfactory. We aimed to evaluate the effects of metformin (MET) and pioglitazone (PIO) combination on apoptosis and AMP-activated protein kinase/mammalian target of rapamycin (mTOR) signaling pathway in human anaplastic thyroid cancer cells. In this study, we evaluated the effects of MET and PIO individually and the combination of the two drugs on the cellular lines SW1736 and C643 ATC. Genes contained in the mTOR signaling pathway were examined using human mTOR Signalization RT2 Profiler PCR Array. In C643 and SW1736 cell lines, IC50 doses of MET and PIO were found out as 17.69 mM, 11.64 mM, 27.12 µM, and 23.17 µM. Also, the combination of MET and PIO was determined as an additive according to isobologram analyses. We have found the downregulation of the expression levels of oncogenic genes: AKT3, CHUK, CDC42, EIF4E, HIF1A, IKBKB, ILK, MTOR, PIK3CA, PIK3CG, PLD1, PRKCA, and RICTOR genes, in the MET and PIO combination-treated cells. In addition, expression levels of tumor suppressor genes, DDIT4, DDIT4L, EIF4EBP1, EIF4EBP2, FKBP1A, FKBP8, GSK3B, MYO1C, PTEN, ULK1, and ULK2, were found to have increased significantly. The MET + PIO combination was first applied to thyroid cancer cells, and significant reductions in the level of oncogenic genes were detected. The decreases, particularly, in AKT3, DEPTOR, EIF4E, ILK, MTOR, PIK3C, and PRKCA expressions indicate that progression can be prevented in thyroid cancer cells and these genes could be selected as therapeutic targets. © 2020 Wiley Periodicals LLC
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AMP-Activated Protein Kinases , Apoptosis , Cell Line, Tumor , Drug Therapy, Combination , Gene Expression , Humans , Metformin , Pioglitazone , Signal Transduction , Thyroid Carcinoma, Anaplastic , Thyroid Neoplasms , TOR Serine-Threonine Kinases , akt3 protein , conserved helix loop helix ubiquitous kinase , ddit4 protein , ddit4l protein , eif4ebp1 protein , eif4ebp2 protein , fk506 binding protein 8 , fkbp1a protein , glycogen synthase kinase 3beta , hypoxia inducible factor 1alpha , I kappa B kinase beta , initiation factor 4E , integrin linked kinase , mammalian target of rapamycin , metformin , myo1c protein , phosphatidylinositol 3,4,5 trisphosphate 3 phosphatase , phospholipase D1 , phosphotransferase , pik3ca protein , pik3cg protein , pioglitazone , prkca protein , protein Cdc42 , rapamycin-insensitive companion of mTOR , serine threonine protein kinase ULK1 , serine threonine protein kinase ULK2 , tumor suppressor protein , unclassified drug , hydroxymethylglutaryl coenzyme A reductase kinase , metformin , MTOR protein, human , pioglitazone , target of rapamycin kinase , AMPK signaling , anaplastic thyroid carcinoma , apoptosis , Article , C-643 cell line , cell viability , combination index , controlled study , down regulation , drug mechanism , evaluation study , gene expression level , human , human cell , IC50 , mTOR signaling , SW1736 cell line , WST-1 assay , apoptosis , combination drug therapy , drug effect , gene expression , metabolism , pathology , signal transduction , thyroid carcinoma , thyroid tumor , tumor cell line