Inducible Hsp70 in the Regulation of Cancer Cell Survival: Analysis of Chaperone Induction, Expression and Activity

Abstract

Understanding the mechanisms that control stress is central to realize how cells respond to environmental and physiological insults. All the more important is to reveal how tumour cells withstand their harsher growth conditions and cope with drug-induced apoptosis, since resistance to chemotherapy is the foremost complication when curing cancer. Intensive research on tumour biology over the past number of years has provided significant insights into the molecular events that occur during oncogenesis, and resistance to anti-cancer drugs has been shown to often rely on stress response and expression of inducible heat shock proteins (HSPs). However, with respect to the mechanisms guarding cancer cells against proteotoxic stresses and the modulatory effects that allow their survival, much remains to be defined. Heat shock proteins are molecules responsible for folding newly synthesized polypeptides under physiological conditions and misfolded proteins under stress, but their role in maintaining the transformed phenotype often goes beyond their conventional chaperone activity. Expression of inducible HSPs is known to correlate with limited sensitivity to apoptosis induced by diverse cytotoxic agents and dismal prognosis of several tumour types, however whether cancer cells survive because of the constitutive expression of heat shock proteins or the ability to induce them when adapting to the hostile microenvironment remains to be elucidated. Clear is that tumours appear nowadays more “addicted” to heat shock proteins than previously envisaged, and targeting HSPs represents a powerful approach and a future challenge for sensitizing tumours to therapy. This review will focus on the anti-apoptotic role of heat shock 70kDa protein (Hsp70), and how regulatory factors that control inducible Hsp70 synthesis, expression and activity may be relevant for response to stress and survival of cancer cells.

Targeting the STAT3 signaling pathway in cancer: Role of synthetic and natural inhibitors

“…Hsp70 prevents JNK-induced phosphorylation and inhibition of Bcl-2 and Bcl-xL anti-apoptotic proteins and promotes cell survival through the maintenance of mitochondria stability. STAT3 can bind to specific sequences at the Hsp70 promoter (5′-CTGGRA-3′) and is responsible for Hsp70 synthesis in cancer cells, mediating the expression of antiapoptotic proteins [153].…”

Targeting Hsp70: A possible therapy for cancer

“…Furthermore, Hsp70 blocks NF-kB-activation through inhibition of I-kB-α kinase (IKK) and degradation of I-kB-α [69,70]. Hsp70 may also facilitate the elimination of DNA-damaged cells [71]. Inhibitor of growth (ING) proteins acts as tumor suppressors; their expression is down-regulated in human cancers that transmit a death signal and bind to histones and therefore control chromatin remodeling and p53 activity [72,73].…”

The Effect of Structure and Mechanism of the Hsp70 Chaperone on the Ability to Identify Chemical Modulators and Therapeutics

“…tBid also signals a conformational shift in cytosolic BAX (proapoptotic protein from the Bcl-2 family), which triggers association with the mitochondrial membrane [158]. In the presence of Hsp70, JNK phosphorylation, Bid cleavage, and BAX membrane association can all be inhibited, each in turn stopping the release of cytochrome c from the mitochondria [159][160][161].…”