Targeting Hsp70: A possible therapy for cancer

Abstract

In all organisms, heat-shock proteins (HSPs) provide an ancient defense system. These proteins act as molecular chaperones by assisting proper folding and refolding of misfolded proteins and aid in the elimination of old and damaged cells. HSPs include Hsp100, Hsp90, Hsp70, Hsp40, and small HSPs. Through its substrate-binding domains, Hsp70 interacts with wide spectrum of molecules, ranging from unfolded to natively folded and aggregated proteins, and provides cytoprotective role against various cellular stresses. Under pathophysiological conditions, the high expression of Hsp70 allows cells to survive with lethal injuries. Increased Hsp70, by interacting at several points on apoptotic signaling pathways, leads to inhibition of apoptosis. Elevated expression of Hsp70 in cancer cells may be responsible for tumorigenesis and for tumor progression by providing resistance to chemotherapy. In contrast, inhibition or knockdown of Hsp70 reduces the size of tumors and can cause their complete regression. Moreover, extracellular Hsp70 acts as an immunogen that participates in cross presentation of MHC-I molecules. The goals of this review are to examine the roles of Hsp70 in cancer and to present strategies targeting Hsp70 in the development of cancer therapeutics.

Keywords: Apoptosis; Cancer therapeutics; Hsp70; Immunogenicity.

Fig. 1

Structure of Hsp70 with sites of action [–23]. N-terminal shows ATPase domain with associated co-chaperones (Bag1/Hip/hsp110 or hspBP1). However, C-terminal represents EEVD domain with its co-chaperone (Hop/Hdj-1/Chip) and peptide binding domain. J-domain localizes in the central approximately.

Fig. 2

Diagrammatic presentation of the chaperone functions of Hsp70 [–23,25]. Hsp70 binds to unfolded protein in the presence of J-proteins using ATP. ATP hydrolysis stimulates J-protein release that further led to release of correctly folded protein(s) and Hsp70 become available for next cycle.

Fig. 3

Schematic representation of the function of Hsp70 in the apoptotic signaling and survival pathways [–38]. SAPKs stimulate synthesis of Hsp70 that leads to cell survival. High Hsp70 interferes at several levels in the apoptotic signaling such as apoptosome, caspases, and cathepsins. Hsp70 also contributes in heterodimerization of bcl2 and Bcl-xL that block Bax heterodimerization.

Fig. 4

Schematic representation of the inhibition of Hsp70 in cell survival pathways [–163]. Hsp70 can be inhibited at transcription and post-transcription levels as indicated in the figure. Inhibition of Hsp70 may results in induction of cell death.

Fig. 5

Diagram depicting involvement of Hsp 70 in cross presentation [–163]. Receptor mediated endocytosis of Hsp70 was presented by MHC-II in association with CD4⁺ T cells. However, small fragments of Hsp70 was presented by MHC-I molecule in association with CD8⁺ T cells, called “cross presentation”.