The Roles of Two Isoforms of Heat Shock Protein Hsp90 in the Resistance of Human Fibrosarcoma HT1080 Cells to Hsp90 Inhibitors and Cytoxic Drugs

Abstract

Intracellular heat shock protein 90 (Hsp90) performs important functions related to the folding, stabilization, and degradation of various proteins in the cell, and prevents protein aggregation and denaturation under various types of stress. There are two isoforms of Hsp90, that is, the inducible Hsp90α isoform and the constitutive Hsp90β isoform. Hsp90β is thought to play a key role in the functioning of housekeeping proteins, while Hsp90α plays an important role in the cellular response to stress. We explored the roles of two Hsp90 isoforms in the resistance of human HT1080 fibrosarcoma cells to Hsp90 inhibitors and a number of antitumor drugs with different mechanisms of action for the first time. Both Hsp90 isoforms have been shown to make a comparable contribution to cell resistance to Hsp90 inhibitors and one Hsp90 isoform is not able to completely compensate for the absence of another Hsp90 isoform under the influence of Hsp90 inhibitors. Both Hsp90 isoforms are also involved in cell resistance to cytotoxic anticancer drugs, with Hsp90α likely playing a more important role than Hsp90β in protecting cells from the cytotoxic effects of sorafemib and nocodazole. For cisplatin, each of the Hsp90 isoforms is able to largely compensate for the absence of the other isoform. For doxorubicin, bortezomib, sorafenib, paclitaxel, and nocodazole, the absence of one of the Hsp90 isoforms led to a significant decrease in cell resistance to anticancer drugs, which was especially pronounced in the case of paclitaxel and nocodazole. The Hsp90 inhibitor 17-AAG potentiates the effect of cytotoxic drugs on cells, providing the most pronounced synergy with paclitaxel and nocodazole. As a result, the important role of both Hsp90 isoforms in cell resistance to Hsp90 inhibitors and anticancer drugs with different mechanisms of action was determined for the first time. The data we obtained indicate the prospects of developing Hsp90α- or Hsp90β-specific inhibitors for antitumor therapy and their combined use with known antitumor drugs.