Targeting Heat Shock Proteins 70/90 and Proteasome for Cancer Therapy

Abstract

Recent progresses in cancer therapy suggest the importance of targeting more than one protein targets or signaling pathways. In events of stresses including the therapeutic treatments, damaged proteins are either repaired by heat shock proteins or ubiquitin-tagged for proteasome-dependent protein degradation. Heat shock proteins mediated protein protection and cell signaling, as well as the ubiquitin-proteasomal degradation are thus central to cellular homeostasis, and are reported to play substantial roles in tumor cells' rapid-metabolism and stimuli-resistance. The up-regulated heat shock protein 90 (HSP90), heat shock protein 70 (HSP70) and 26S proteasome in cancer cells have been thereby recognized as important drug targets and are under intensive studies in recent years. While most research focuses on each target in a separate manner, simultaneous inhibition of more than one target results in an enhanced efficacy, especially in single-drug-resistant cancer cell line. In this review, current development of chemical inhibitors for these three core targets is summarized respectively and the progress on related simultaneous inhibitions has been discussed. In a perspective view, combined inhibitions of HSP 90/70 and the 26S proteasome could be a promising approach in cancer therapy and may suggest a future direction for drug-screening.

Inhibition of nestin suppresses stem cell phenotype of glioblastomas through the alteration of post-translational modification of heat shock protein HSPA8/HSC71

“…Anticancer drug development strategies critically involve the identification of novel molecular targets which are crucial for tumorigenesis and metastasis. Heat shock proteins (HSPs) have gained interest as a promising anticancer drug target, due to its importance in maintaining the stability, integrity, conformation and function of key oncogenic proteins, including HSP90 [39], HSP70 [40], HSP 40 family member, DnaJ homolog, subfamily B, member 8 [41]. Hsp90 inhibitors have now progressed to phase I/II clinical testing [42].…”

Examination of Gossypol-Pluronic Micelles as Potential Radiosensitizers

“…However, inhibition of Hsp 90 is reported to trigger the upregulation of Hsp 70. Therefore, dual inhibition of Hsp 90 and 70, such as that exhibited by Pluronic L10, is considered to be more attractive for cancer therapy (28)(29)(30)(31)(32). In this study, F88, P85, L35, and P123 were selected as representative Pluronics in group I, II, IIIa, and IIIb, respectively.…”

Chaperone molecules concentrate together with the ubiquitin–proteasome system inside particulate cytoplasmic structures: possible role in metabolism of misfolded proteins

“…Present findings point to PaCSs as an integrated, active UPS center well equipped for metabolism of misfolded proteins, especially in cells under physiological (fetal development) or pathological (neoplasia or inflammation) stress. 2011Sommi et al 2013). However, the accumulation of polyubiquitinated proteins in PaCSs also suggests some malfunction or insufficiency of the 26S proteasome component, which is required for rapid degradation of such proteins (Navon and Ciechanover 2009).…”

“…There is a close interaction of newly synthesized proteins with chaperone molecules such as Hsp40, Hsp70, and Hsp90 (Mayer and Bukau 2005;Wang 2011). Indeed, Hsp40 and Hsp70 have a special role in handling misfolded or conformationally metastable proteins, thus determining their fate, that is, appropriate folding or UPS-dependent degradation (Douglas et al 2009;McClellan et al 2005;Young 2010).…”

“…Indeed, Hsp40 and Hsp70 have a special role in handling misfolded or conformationally metastable proteins, thus determining their fate, that is, appropriate folding or UPS-dependent degradation (Douglas et al 2009;McClellan et al 2005;Young 2010). However, Hsp90 has been found to prevent proteasome-dependent degradation of misfolded polyubiquitinated proteins, especially in neoplasms (Neckers 2006;Wang 2011), potentially causing proteasome dysfunction. Thus, a search for Hsp90 inside PaCSs might explain the proteasome inability to degrade completely polyubiquitinated proteins.…”