laq824 and Stomach-Neoplasms

The molecular basis of the antitumor selectivity of histone deacetylase inhibitors (HDIs) remains unclear. Centrosomal Aurora-A kinase regulates chromosomal segregation during mitosis. The overexpression or amplification of Aurora-A leads to genetic instability, and its inhibition has shown significant antitumor effects. In this paper, we report that structurally related hydroxamate LAQ824 and SK-7068 induce tumor-selective mitotic defects by depleting Aurora-A. We found that HDI-treated cancer cells, unlike nontransformed cells, exhibit defective mitotic spindles. After HDI, Aurora-A was selectively downregulated in cancer cells, whereas Aurora-B remained unchanged in both cancer and nontransformed cells. LAQ824 or SK-7068 treatment inhibited histone deacetylase (HDAC) 6 present in Aurora-A/heat shock protein (Hsp) 90 complex. Inhibition of HDAC6 acetylated Hsp90 and resulted in dissociation of acetylated Hsp90 from Aurora-A. As a result, Hsp70 binding to Aurora-A was enhanced in cancer cells, leading to proteasomal degradation of Aurora-A. Overall, these provide a novel molecular basis of tumor selectivity of HDI. LAQ824 and SK-7068 might be more effective HDIs in cancer cells with Aurora-A overexpression.

Topics: Antineoplastic Agents; Aurora Kinase B; Aurora Kinases; Biphenyl Compounds; Cell Death; Cell Line, Tumor; Enzyme Inhibitors; Histone Deacetylase 6; Histone Deacetylase Inhibitors; Histone Deacetylases; HSP70 Heat-Shock Proteins; HSP90 Heat-Shock Proteins; Humans; Hydroxamic Acids; Protein Serine-Threonine Kinases; Pyrrolidines; Stomach Neoplasms