Heat shock proteins in cancer.pdf

Heat shock proteins in cancer: chaperones of tumorigenesis Stuart K. Calderwood1,3, Md Abdul Khaleque1, Douglas B. Sawyer3 and Daniel R. Ciocca2 1Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA 2Institute of experimental Medicine and Biology of Cuyo (CRICYT-CONICET) and Argentine Foundation for Cancer Research (FAIC), Mendoza 5500, Argentina 3Boston University School of Medicine, Boston, MA 02118, USAThe heat shock proteins (HSPs) induced by cell stress are expressed at high levels in a wide range of tumors and are closely associated with a poor prognosis and resistance to therapy. The increased transcription of HSPs in tumor cells is due to loss of p53 function and to higher expression of the proto-oncogenes HER2 and c-Myc, and is crucial to tumorigenesis. The HSP family members play overlapping, essential roles in tumor growth both by promoting autonomous cell prolifer- ation and by inhibiting death pathways. The HSPs have thus become targets for rational anti-cancer drug design: HSP90 inhibitors are currently showing much promise in clinical trials, whereas the increased expression of HSPs in tumors is forming the basis of chaperone-based immunotherapy.Introduction Heat shock proteins (HSPs) are the products of several distinct gene families that are required for cell survival during stress and are named according to the approximate relative molecular mass (Mr) of their encoded proteins, including HSP10, HSP27, HSP40, HSP60, HSP70, HSP90 and HSP110 [1–4] (Table 1). The cytoprotective properties of the HSPs are closely linked to their primary functions as molecular chaperones [1,5,6]. The intracellular reactions catalyzed by the HSPs, which led to their designation as molecular chaperones, are divided into two main categories described as ‘protein holding’ and ‘protein folding’ [7,8]. The principal holding proteins belong to the HSP70 and HSP90 families, which bind to unfolded sequences in polypeptide substrates and show prefere