HSP70 Multi-Functionality in Cancer

Abstract

The 70-kDa heat shock proteins (HSP70s) are abundantly present in cancer, providing malignant cells selective advantage by suppressing multiple apoptotic pathways, regulating necrosis, bypassing cellular senescence program, interfering with tumor immunity, promoting angiogenesis and supporting metastasis. This direct involvement of HSP70 in most of the cancer hallmarks explains the phenomenon of cancer “addiction” to HSP70, tightly linking tumor survival and growth to the HSP70 expression. HSP70 operates in different states through its catalytic cycle, suggesting that it can multi-function in malignant cells in any of these states. Clinically, tumor cells intensively release HSP70 in extracellular microenvironment, resulting in diverse outcomes for patient survival. Given its clinical significance, small molecule inhibitors were developed to target different sites of the HSP70 machinery. Furthermore, several HSP70-based immunotherapy approaches were assessed in clinical trials. This review will explore different roles of HSP70 on cancer progression and emphasize the importance of understanding the flexibility of HSP70 nature for future development of anti-cancer therapies.

Advances in Exosomes‐Based Drug Delivery Systems

“…In addition, HSP70 acts as an immune stimulatory factor with potential use in cancer vaccines. [141,142] An approach for targeting tumorderived exosomes using the HSP70 aptamer has been developed. This aptamer allows for the capturing of HSP70-positive exosomes in blood or urine samples from patients with different types of cancer.…”

Association of Plasma Heat Shock Protein 70 with Disease Severity, Smoking and Lung Function of Patients with Chronic Obstructive Pulmonary Disease

“…The 72-kDa Hsp (Hsp70 in the following refers to this protein) is located in the cytosol and nucleus, and its expression is induced as a part of the response to different stressors like heat, bacterial or viral infections [ 6 , 7 ]. However, apart from being an intracellular protein, Hsp70 can be released from cells passively following cellular lysis i.e., necrotic death, and/or actively through nonclassical exocytotic pathways [ 8 , 9 , 10 ]. When found in the extracellular milieu, Hsp70 becomes a damage-associated molecular pattern (DAMP) and represents a danger signal to the immune system [ 11 ].…”

“…eHsp70 acts mainly as proinflammatory and activates immune responses by engaging appropriate receptors (toll-like receptors (TLRs) 2 and 4, cluster of differentiation (CD) 14, CD40, CD91, lectin-like oxidized low-density lipoprotein-1 (LOX-1), receptor for advanced glycation end-products (RAGE)) [ 9 , 12 , 13 ]. On the other hand, eHsp70 might also modulate an adaptive immune response through binding to antigenic peptides and presenting them to antigen-presenting cells [ 14 ].…”

Extracellular heat shock proteins and cancer: New perspectives

“…HSP co-chaperone profile varies between EVs derived from different sample sources ( Table 3 ). EV cargos derived from melanoma tissue contain major HSP90 co-chaperones and all five types of molecular co-chaperones critical for regulation of HSP70 functional cycle: DNAJ/HSP40 molecules deliver client proteins to HSP70, nucleotide-exchange factors (HSPH1, HSPBP1, SIL1, GRPEL1, BAG) stabilize open conformation of HSP70, HSP70 interacting protein (HIP/ST13) delays peptide release from HSP70, STIP1/ HOP co-chaperone transfers client proteins from HSP70 to HSP90 while C-terminus of HSP70 interacting protein (CHIP/STUB1) co-chaperone mediates degradation of HSP70 client proteins ( Table 3 ) [189] , [190] , [191] , [192] , [193] , [194] , [195] , [196] . Interestingly, EVs isolated from plasma of melanoma patients contained two HSP70 co-chaperones HSPA4/HSPH2 and ST13/HIP, and no HSP90 co-chaperones were observed, whereas EVs derived from lymphatic drainage of the matched patients showed to carry more members of HSP70 network ( Table 3 ) [174] .…”