tubacin and 17-(dimethylaminoethylamino)-17-demethoxygeldanamycin

The deleterious effects of glucocorticoids on glucose homeostasis limit their clinical use. There is substantial evidence demonstrating that islet function impaired by long-term glucocorticoids exposure is a core defect in the progression of impaired glucose tolerance to diabetes. The activity of heat-shock protein (Hsp) 90 is required to maintain the hormone-binding activity and stability of glucocorticoid receptor (GR). In the present study, Hsp90 inhibition by 17-DMAG counteracted dexamethasone-mediated inhibition of glucose-stimulated insulin secretion in isolated rat islets as well as expressions of neuropeptide Y (NPY) and somatostatin receptor 3 (SSTR3), two negative regulators of insulin secretion. Like 17-DMAG, both the pan-histone deacetylase (HDAC) inhibitor TSA and HDAC6 inhibitor Tubacin exhibited a similar action in protecting islet function against dexamethasone-induced injury, along with the downregulation of NPY and SSTR3 expressions. The hyperacetylation of Hsp90 by TSA and Tubacin disrupted its binding ability to GR and blocked dexamethasone-elicited nuclear translocation of GR in INS-1 β-cell lines. In addition, Tubacin treatment triggered the GR protein degradation through the ubiquitin-proteasome pathway. These findings suggest that Hsp90 acetylation by inhibiting HDAC6 activity may be a potential strategy to prevent the development of steroid diabetes mellitus via alleviating glucocorticoid-impaired islet function.

Topics: Acetylation; Anilides; Animals; Benzoquinones; Cell Line; Dexamethasone; Glucocorticoids; Histone Deacetylase 6; Histone Deacetylase Inhibitors; HSP90 Heat-Shock Proteins; Hydroxamic Acids; Insulin; Islets of Langerhans; Lactams, Macrocyclic; Male; Proteasome Endopeptidase Complex; Protein Processing, Post-Translational; Proteolysis; Rats, Sprague-Dawley; Secretory Pathway; Tissue Culture Techniques

Breast cancer is the leading cause of women death. Heat shock protein 90 (HSP90) and Histone deacetylase 6 (HDAC6) are promising anti-cancer drug targets. However, it's still unclear the applicability of anti-HSP90 and anti-HDAC6 strategies in precision treatment of breast cancer. In current study, we found that triple negative breast cancer (TNBC) cells, compared to T47D, an ERα+ breast cancer cell line, exhibited 7~40 times lower IC

Topics: Acetylation; Anilides; Animals; Antineoplastic Agents; Apoptosis; Benzoquinones; Cell Cycle; Cell Line, Tumor; Cell Survival; Estradiol; Female; Fulvestrant; Histone Deacetylase 6; Histone Deacetylase Inhibitors; HSP90 Heat-Shock Proteins; Humans; Hydroxamic Acids; Immunohistochemistry; Lactams, Macrocyclic; Mice; Tamoxifen; Triple Negative Breast Neoplasms