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. Non-proliferating 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/co-chaperone 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.

Regional Centre for Applied Molecular Oncology Masaryk Memorial Cancer Institute Zluty kopec 7 Brno 656 53 Czech Republic

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Ciocca D.R., Calderwood S.K. Heat shock proteins in cancer: diagnostic, prognostic, predictive, and treatment implications. Cell Stress Chaperones. 2005;10:86–103. doi: 10.1379/CSC-99r.1. PubMed DOI PMC

Workman P. Altered states: selectively drugging the Hsp90 cancer chaperone. Trends Mol. Med. 2004;10:47–51. doi: 10.1016/j.molmed.2003.12.005. PubMed DOI

Hernandez M.P., Sullivan W.P., Toft D.O. The assembly and intermolecular properties of the hsp70-Hop-hsp90 molecular chaperone complex. J. Biol. Chem. 2002;277:38294–38304. doi: 10.1074/jbc.M206566200. PubMed DOI

Kubota H., Yamamoto S., Itoh E., Abe Y., Nakamura A., Izumi Y., Okada H., Iida M., Nanjo H., Itoh H., Yamamoto Y. Increased expression of co-chaperone HOP with HSP90 and HSC70 and complex formation in human colonic carcinoma. Cell Stress Chaperones. 2010;15:1003–1011. doi: 10.1007/s12192-010-0211-0. PubMed DOI PMC

Sun W., Xing B., Sun Y., Du X., Lu M., Hao C., Lu Z., Mi W., Wu S., Wei H., Gao X., Zhu Y., Jiang Y., Qian X., He F. Proteome analysis of hepatocellular carcinoma by two-dimensional difference gel electrophoresis: novel protein markers in hepatocellular carcinoma tissues. Mol. Cell. Proteomics. 2007;6:1798–1808. doi: 10.1074/mcp.M600449-MCP200. PubMed DOI

Erlich R.B., Kahn S.A., Lima F.R., Muras A.G., Martins R.A., Linden R., Chiarini L.B., Martins V.R., Moura Neto V. STI1 promotes glioma proliferation through MAPK and PI3K pathways. Glia. 2007;55:1690–1698. doi: 10.1002/glia.20579. PubMed DOI

Kajiro M., Hirota R., Nakajima Y., Kawanowa K., So-ma K., Ito I., Yamaguchi Y., Ohie S.H., Kobayashi Y., Seino Y., Kawano M., Kawabe Y., Takei H., Hayashi S., Kurosumi M., Murayama A., Kimura K., Yanagisawa J. The ubiquitin ligase CHIP acts as an upstream regulator of oncogenic pathways. Nat. Cell. Biol. 2009;11:312–319. doi: 10.1038/ncb1839. PubMed DOI

Kundrat L., Regan L. Balance between folding and degradation for Hsp90-dependent client proteins: a key role for CHIP. Biochemistry. 2010;49:7428–7438. doi: 10.1021/bi100386w. PubMed DOI PMC

Scheufler C., Brinker A., Bourenkov G., Pegoraro S., Moroder L., Bartunik H., Hartl F.U., Moarefi I. Structure of TPR domain-peptide complexes: critical elements in the assembly of the Hsp70-Hsp90 multichaperone machine. Cell. 2000;101:199–210. doi: 10.1016/S0092-8674(00)80830-2. PubMed DOI

Muller P., Hrstka R., Coomber D., Lane D.P., Vojtesek B. Chaperone-dependent stabilization and degradation of p53 mutants. Oncogene. 2008;27:3371–3383. doi: 10.1038/sj.onc.1211010. PubMed DOI

Banks L., Matlashewski G., Crawford L. Isolation of human-p53-specific monoclonal antibodies and their use in the studies of human p53 expression. Eur. J. Biochem. 1986;159:529–534. doi: 10.1111/j.1432-1033.1986.tb09919.x. PubMed DOI

Trepel J., Mollapour M., Giaccone G., Neckers L. Targeting the dynamic HSP90 complex in cancer. Nat. Rev. Cancer. 2010;10:537–549. doi: 10.1038/nrc2887. PubMed DOI PMC

Pick E., Kluger Y., Giltnane J.M., Moeder C., Camp R.L., Rimm D.L., Kluger H.M. High HSP90 expression is associated with decreased survival in breast cancer. Cancer Res. 2007;67:2932–2937. doi: 10.1158/0008-5472.CAN-06-4511. PubMed DOI

Li C.F., Huang W.W., Wu J.M., Yu S.C., Hu T.H., Uen Y.H., Tian Y.F., Lin C.N., Lu D., Fang F.M., Huang H.Y. Heat shock protein 90 overexpression independently predicts inferior disease-free survival with differential expression of the alpha and beta isoforms in gastrointestinal stromal tumors. Clin. Cancer Res. 2008;14:7822–7831. doi: 10.1158/1078-0432.CCR-08-1369. PubMed DOI

Kang G.H., Lee E.J., Jang K.T., Kim K.M., Park C.K., Lee C.S., Kang D.Y., Lee S.H., Sohn T.S., Kim S. Expression of HSP90 in gastrointestinal stromal tumours and mesenchymal tumours. Histopathology. 2010;56:694–701. doi: 10.1111/j.1365-2559.2010.03550.x. PubMed DOI

Stankiewicz M., Nikolay R., Rybin V., Mayer M.P. CHIP participates in protein triage decisions by preferentially ubiquitinating Hsp70-bound substrates. FEBS J. 2010;277:3353–3367. doi: 10.1111/j.1742-4658.2010.07737.x. PubMed DOI

Santagata S., Hu R., Lin N.U., Mendillo M.L., Collins L.C., Hankinson S.E., Schnitt S.J., Whitesell L., Tamimi R.M., Lindquist S., Ince T.A. High levels of nuclear heat-shock factor 1 (HSF1) are associated with poor prognosis in breast cancer. Proc. Natl. Acad. Sci. USA. 2011;108:18378–18383. doi: 10.1073/pnas.1115031108. PubMed DOI PMC

Dai C., Whitesell L., Rogers A.B., Lindquist S. Heat shock factor 1 is a powerful multifaceted modifier of carcinogenesis. Cell. 2007;130:1005–1018. doi: 10.1016/j.cell.2007.07.020. PubMed DOI PMC

Zou J., Guo Y., Guettouche T., Smith D.F., Voellmy R. Repression of heat shock transcription factor HSF1 activation by HSP90 (HSP90 complex) that forms a stress-sensitive complex with HSF1. Cell. 1998;94:471–480. doi: 10.1016/S0092-8674(00)81588-3. PubMed DOI

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