herbimycin and Thyroid-Neoplasms

The aim of the present study was to evaluate the effect of heat-shock protein 90 (HSP90) inhibitors, 17-allylamino-17-demethoxygeldanamycin (17-AAG) and herbimycin A (HMA) on survival of anaplastic thyroid carcinoma (ATC) cells.. Antitumor activities of 17-AAG and HMA were investigated in FRO ATC cells.. In FRO ATC cells, 17-AAG and HMA caused cell death with concomitant changes in the expression of HSP90 client proteins, increased β-catenin protein levels, and inhibited PI3K/AKT signaling. The inactivation of β-catenin by β-catenin siRNA transfection and the activation of PI3K/AKT signaling by p110α plasmid transfection abrogated cell death caused by 17-AAG and HMA.. 17-AAG and HMA have cytotoxic activities accompanied by regulation of HSP90 client proteins, and cytotoxicity is associated with overexpression of β-catenin and suppression of PI3K/AKT signaling in FRO ATC cells.

Topics: Antibiotics, Antineoplastic; Benzoquinones; beta Catenin; Cell Death; Cell Line, Tumor; Gene Expression Regulation, Neoplastic; HSP90 Heat-Shock Proteins; Humans; Lactams, Macrocyclic; Proto-Oncogene Proteins c-akt; Rifabutin; Signal Transduction; Thyroid Carcinoma, Anaplastic; Thyroid Neoplasms

We aimed to elucidate the effect of herbimycin A (HMA), a heat shock protein 90 inhibitor, on cell growth and epithelial-mesenchymal transition (EMT) in anaplastic thyroid carcinoma (ATC) cells. HMA inhibited cell growth and migration concomitantly with increase of E-cadherin as well as decrease of N-cadherin and vimentin. Moreover, HMA upregulated p21 and p27, while it downregulated p53 and Akt. In HMA-treated condition, knockdown of E-cadherin and overexpression of p53 increased N-cadherin and vimentin, and mitigated the inhibitory effects of HMA on cell growth and migration. Furthermore, knockdown of p21 and p27 ameliorated inhibition of cell growth and reversal of EMT. In addition, the activation of Akt attenuated growth inhibition, cell death and EMT reversal. Therefore, we propose that HMA suppresses cell growth, and reverses EMT in conjunction with the activation of E-cadherin, p21 and p27 and the inactivation of p53 and PI3K/Akt signaling in ATC cells.

Topics: Antigens, CD; Cadherins; Cell Death; Cell Line, Tumor; Cell Movement; Cell Proliferation; Epithelial-Mesenchymal Transition; Flow Cytometry; Gene Silencing; Humans; Plasmids; Rifabutin; RNA, Small Interfering; Thyroid Carcinoma, Anaplastic; Thyroid Neoplasms; Tumor Suppressor Protein p53; Wound Healing

We examined the effect of herbimycin A, a potent inhibitor of tyrosine kinases, on NIH(ret) cells and TPC-1 papillary thyroid carcinoma cells, both of which express the active ret genes. Herbimycin A reversed the morphology of NIH(ret) cells to flat cells with a concomitant reassembly of microfilament bundles. On the other hand, it did not induce a significant change in cell shape of TPC-1 cells. When tyrosine kinase activities of the active ret gene products in herbimycin A-treated NIH(ret) and TPC-1 cells were examined in immunocomplex kinase assays, they drastically decreased in both cells as compared with untreated cells. In addition, herbimycin A strongly inhibited tyrosine phosphorylation of 40 kDa and 31 kDa proteins present in the immunoprecipitates of both cells, suggesting that these proteins could associate with the Ret proteins.

Topics: Actins; Amino Acids; Benzoquinones; Cell Line; Drosophila Proteins; Humans; Lactams, Macrocyclic; Phosphoproteins; Phosphorylation; Protein-Tyrosine Kinases; Proto-Oncogene Proteins; Proto-Oncogene Proteins c-ret; Proto-Oncogenes; Quinones; Receptor Protein-Tyrosine Kinases; Rifabutin; Thyroid Neoplasms; Tumor Cells, Cultured