Hsp70: A Cancer Target Inside and Outside the Cell

Abstract

Heat shock protein 70 (Hsp70) is the most ubiquitous stress-inducible chaperone. It accumulates in the cells in response to a wide variety of physiological and environmental insults including anticancer chemotherapy, thus allowing the cell to survive to lethal conditions. Intracellular Hsp70 is viewed as a cytoprotective protein. Indeed, this protein can inhibit key effectors of the apoptotic and autophagy machineries. In cancer cells, the expression of Hsp70 is abnormally high, and Hsp70 may participate in oncogenesis and in resistance to chemotherapy. In rodent models, Hsp70 overexpression increases tumor growth and metastatic potential. Depletion or inhibition of Hsp70 frequently reduces the size of the tumors and can even cause their complete involution. However, HSP70 is also found in the extra-cellular space where it may signal via membrane receptors or endosomes to alter gene transcription and cellular function. Overall, Hsp70 extracellular function is believed to be immnunogenic and the term chaperokine to define the extracellular chaperones such as Hsp70 has been advanced. In this chapter the knowledge to date, as well as some emerging paradigms about the intra- and extra-cellular functions of Hsp70, are presented. The strategies targeting Hsp70 that are being developed in cancer therapy will also be discussed.

Molecular Chaperones in Cancer Stem Cells: Determinants of Stemness and Potential Targets for Antitumor Therapy

“…Both those publications [124,125] describe artificially modeled situations, but it provides indirect evidence that extracellular (secreted) HSP70 can drive cancer cells to EMT-and CSC-like phenotypes. In support of this, there are data that cancer cells do secrete HSP70 [56,114].…”

“…The role of HSP70 in oncogenesis is of extreme importance and most human malignancies exhibit increased HSP70 expression; the latter is often correlated with tumor aggressiveness and poor tumor response to therapeutics [40,57,113]. Interestingly, cancer cells can expose HSP70 on their surface and secrete it out [57,114]. A contribution of intracellular and extracellular HSP70 to the cancer cell stemness is considered herein.…”

2-phenylethynesulfonamide inhibits growth of oral squamous cell carcinoma cells by blocking the function of heat shock protein 70

“…Increasing evidence indicates that Hsp70 may be a novel therapeutic target for cancer treatment, as Hsp70 is involved in cancer growth, metastasis, and development [19]. In the present study, PES, a specific Hsp70 inhibitor, effectively PES, the biologic function of a small molecular Hsp70 inhibitor, is found to be effective against various cancers [9,20,21].…”

Chaperoning STAT3/5 by Heat Shock Proteins: Interest of Their Targeting in Cancer Therapy

“…Stress-inducible HSP70 (also called HSP72 or HSP1A, HSPA1B) is another member of the HSP superfamily that has emerged as a viable and very promising target for development of antitumor drugs to combat various forms of cancer [162][163][164]. As the most ubiquitous stress-inducible chaperone, HSP70 exhibits numerous chaperone functions that are critical for both the folding and proteasomal degradation of misfolded proteins.…”