Alterations of the Hsp70/Hsp90 chaperone and the HOP/CHIP co-chaperone system in cancer

Abstract

Activation of the Hsp90 chaperone system is a characteristic of cancer cells. The regulation of chaperone activities involves their interaction with cochaperones; therefore we investigated the expression of Hsp70 and Hsp90 and their specific co-chaperones HOP and CHIP in cancer cell lines and primary cancers. Inhibition of Hsp90 by 17AAG increased the levels of Hsp70, Hsp90 and HOP but not CHIP mRNA in cancer cells. These changes are linked to activation of the HSF1 transcription factor and we show that the HOP promoter contains HSF1 binding sites, and that HSF1 binding to the HOP promoter is increased following 17AAG. The lack of alteration in the co-chaperone CHIP is explained by a lack of HSF response elements in the CHIP promoter. Nonproliferating cells expressed higher levels of CHIP and lower HOP, Hsp70 and Hsp90 levels compared to proliferating cells. Decreased expression of CHIP in proliferating cancer cells is in keeping with its proposed tumor suppressor properties, while over-expression of HOP in proliferating cells may contribute to excessive Hsp90 activity and stabilization of client proteins in tumors. In a panel of colorectal cancer samples, increased expression of Hsp70 and an increased ratio of HOP to CHIP were found, and were associated with decreased median survival. These data indicate that multiple changes occur in the chaperone/cochaperone system in cancer that impact patient survival. It is likely that the ability to identify individual alterations to this system will be beneficial for treatment strategy decisions, particularly those that employ chaperone inhibitors.

Disruption of prion protein–HOP engagement impairs glioblastoma growth and cognitive decline and improves overall survival

“…17 Two independent studies demonstrated elevated expression of HOP, with Hsp70 or Hsp90, in colon tumors. 18,19 High levels of these proteins have a negative impact on patient survival. 18,19 Elevated HOP expression has been observed in pancreatic and ovarian tumors and in hepatocellular carcinoma.…”

“…18,19 High levels of these proteins have a negative impact on patient survival. 18,19 Elevated HOP expression has been observed in pancreatic and ovarian tumors and in hepatocellular carcinoma. [20][21][22] Secretion of HOP by GBM cells and other cancer cells is thought to influence cell proliferation, invasion and angiogenesis.…”

Oncogene and Non-Oncogene Addiction in Inflammation-Associated Cancers

“…Although a supporting role for HSF1 in an oncogenic melodrama is attractive, a model for non-oncogene addiction with potentially greater ramifications for cancer treatment would argue that cancer cells experience high levels of proteotoxic stress and rely on stress response pathways for survival and proliferation. Cancer cells experience high levels of protein-modifying and metabolic stresses and seem to be particularly dependent on the various actions of HSP70/HSP90 for survival [97,98]. This phenomenon of non-oncogene addiction suggests that it may be possible to target such critical survival proteins for the development of therapies aimed at the selective killing of neoplastic cells.…”

Computational genomic analysis of PARK7 interactome reveals high BBS1 gene expression as a prognostic factor favoring survival in malignant pleural mesothelioma

“…Under oxidative stress conditions, STUB1 along with HSP70 appear to associate and colocalize with PARK7 in cells, indicating that noxious oxidative stimuli lead to PARK7 mitochondrial translocation in a chaperon-dependent manner (53). Modulations of the STUB1-HSP70 system have been observed both in cancer cell lines and primary cancers with possible implications in patient survival (77). In MPM, HSP70 is reported to be upregulated as part of an antiapoptotic, antistress response (27).…”