ver-155008 and Thyroid-Carcinoma--Anaplastic

The aim of the present study was to evaluate the effect of radicicol, an inhibitor of heat shock protein (hsp) 90, alone or in combination with hsp70 inhibition on survival of anaplastic thyroid carcinoma (ATC) cells.. Antitumor activity of radicicol-alone or in combination with the hsp70 inhibitor VER155008 was investigated in 8505C and CAL62 cells.. Radicicol decreased cell viability and Akt protein levels, and increased the percentage of dead cells and hsp70 protein levels. In PIK3CA plasmid-transfected cells, compared to cells treated with radicicol-alone, cell viability increased and cellular death decreased. In cells treated with both radicicol and VER155008, compared to cells treated with radicicol-alone, cell viability further decreased and the percentage of dead cells further increased, with a parallel decrease of the protein levels of heat shock cognate 70, Akt and survivin.. Our results suggest that radicicol induces cell death mediated through PI3K/Akt signaling with modulation of hsp90 client proteins and hsp70 inhibition enhances radicicol-induced cell death with suppression of survivin in ATC cells.

Topics: Cell Death; Cell Line, Tumor; HSP70 Heat-Shock Proteins; Humans; Macrolides; Phosphatidylinositol 3-Kinases; Proto-Oncogene Proteins c-akt; Purine Nucleosides; Signal Transduction; Thyroid Carcinoma, Anaplastic; Thyroid Neoplasms

In this study, we evaluated the effect of the hsp70 inhibitor VER155008 on survival of anaplastic thyroid carcinoma (ATC) cells. In ATC cells, VER155008 increased the percentages of dead cells and vacuolated cells. VER155008 did not lead to the cleavage of caspase-3 protein regardless of pretreatment with z-VAD-fmk. VER155008 increased LC3-II protein levels but the protein levels were not changed by autophagy inhibitors. VER155008 caused the dilatation of endoplasmic reticulum (ER), and the increased mRNA levels of Bip and CHOP, suggesting paraptosis. VER155008-induced paraptosis was attenuated by pretreatment with cycloheximide. In conclusion, VER155008 induces paraptosis characterized by cytoplasmic vacuolation, independence of caspase, dilatation of ER and induction of ER stress markers in ATC cells. Moreover, VER155008-induced paraptosis requires de novo protein synthesis in ATC cells.

Topics: Amino Acid Chloromethyl Ketones; Apoptosis; Autophagy; Caspase 3; Caspase Inhibitors; Cell Line, Tumor; Endoplasmic Reticulum Chaperone BiP; Endoplasmic Reticulum Stress; Heat-Shock Proteins; HSP70 Heat-Shock Proteins; Humans; Microscopy, Electron, Transmission; Neoplasm Proteins; Purine Nucleosides; RNA, Messenger; Thyroid Carcinoma, Anaplastic; Thyroid Neoplasms; Transcription Factor CHOP; Vacuoles