Addiction to chaperones: Probing the role of HSP70 isoforms in cancer cells. (360G-Wellcome-099712_Z_12_Z)

Molecular chaperones assist the efficient folding of proteins, aid the refolding of stress-denatured proteins and prevent the aggregation of damaged peptides. Through these functions molecular chaperones are essential for maintaining protein homeostasis (proteostasis) within the cell (Hartl et al., 2011). Cancer cells have been found to exhibit dependence upon molecular chaperones. Chaperones provide essential support for a malignant lifestyle through the management of stresses imposed on cancer cells as a result of overexpressed and mutated oncoproteins as well as by the adverse microenvironmental conditions present in solid tumours (Galluzzi et al., 2008). The dependence of cancer cells on molecular chaperones makes these proteins an attractive target for drug discovery, exploiting this addiction could aid the development of drugs that selectively target cancer but not healthy cells. Small molecule inhibitors have successfully been developed for the molecular chaperone, Heat Shock Protein 90 (HSP90), which are currently in clinical trials (Neckers and Workman, 2012; Travers et al., 2012). Although the major focus has previously been on HSP90, evidence is now accumulating that the HSP70 family of molecular chaperones is also critical in cancer. HSP70 is antiapoptotic in addition to its role in protein folding and has been found tobe overexpressed in various tumour types including gastric adenocarcinomas (Yoshihara et al., 2006), hepatocarcinomas (Lee et al., 2005) and esophageal cancer (Jazii et al., 2006). Correlations have been described between over-expression of HSP70 and the aggressiveness of several types of cancer. Inaddition HSP70 over-expression in tumours has been linked with therapeutic resistance (Khalil et al, 2011). Previously published work carried out in the laboratory demonstrated that the dual silencing of the HSP70 isoforms, HSP72 and HSC70 causes tumour selective apoptosis and sensitizes malignant cells to HSP90 inhibitors (Powers et al., 2008). It has become clear that a limitation of inhibiting HSP90 is that it causes a mechanism-based activation of the heat shock response leading to the induction of various protective genes including HSP72 and HSC70 (Maloney et al., 2007). HSP70 inhibitors could therefore be valuable as single agents in their own right or extremely effective in combination with HSP90 inhibitors (Powers et al., 2009). The current understanding is that HSP70 plays a key role in the molecular pathogenesis and progression of cancer and is a potential therapeutic target. However, there is much which is not understood about this target. The HSP70 family of molecular chaperones consists of a number of genes which vary in amino acid sequence, cell and tissue localisation and pathology (Daugaard et al., 2007). It is difficult to state the exact number of genes which have been identified within this family as an array of nomenclature is used in the literature. However, a study in which extensive bioinformatic queries were carried out identified 17 genes belonging to the extended HSP70 family in the human genome (Brocchieri et al. 2008). The role and effect of inhibiting each of these targets alone is not well understood. Therefore, the aim of this project is to increase our comprehension of both the basic and translational aspects of HSP70 in cancer, in particular through understanding the role of the different HSP70 isoforms. An improved understanding of the different isoforms of HSP70 will aid in the discovery and development of drugswhich inhibit HSP70.