Proteomic study identified HSP 70 kDa protein 1A as a possible therapeutic target, in combination with histone deacetylase inhibitors, for lymphoid neoplasms

Abstract

Histone deacetylase inhibitors (HDACi) demonstrate possible anticancer activities in various malignancies including lymphoid neoplasms. However, the anticancer effects of HDACi are often limited, and combination therapy with other drugs has been undertaken to improve the outcome of patients. Here we conducted proteomic investigation of 33 lymphoid cell lines to identify novel therapeutic targets for enhancing the effects of HDACi. Using the proteomic data in our published 2D-DIGE database, we examined the proteins associated with resistance to valproic acid (VPA). The lymphoid neoplasm cell lines in the database were grouped according to their sensitivity to VPA treatment. A comparative proteomic study of the cell line groups resulted in the identification of 10 protein spots, whose intensity was associated with chemosensitivity. Among the identified proteins, HSPA1A showed higher expression in cell lines with resistance to VPA, and the results were validated by Western blotting. In vitro experiments demonstrated that treatment with KNK-437, an inhibitor of HSPA1A, enhanced the cytotoxic effects of VPA, as well as vorinostat, in the lymphoid neoplasm cell line. Treatment with KNK-437 facilitated the apoptotic effects of VPA. In conclusion, we identified HSPA1A as a possible therapeutic target, in combination with HDACi, for lymphoid neoplasms.