HSP27: Drug Discovery

Most studies identifying Hsp27 as a possible therapeutic target for the development of appropriate treatment drugs are done on cancer. Thus, extensive literature has been produced that describes the overexpression of heat shock proteins (Hsps) in many types of cancer cells. This poses big challenges for cancer researchers. Firstly it remains to be convincingly determined if the HSF/HSP system is useful as a source of molecular markers to predict which cancer type and patient in particular will be most benefit with an individualized anticancer strategy⁹⁷. Another challenge is to design the most appropriate approach to pharmacologically perturb the HSF/HSP system in order to promote cancer cell killing while minimizing effects on the normal cell. Finally, understanding mechanisms whereby the HSF1 and HSP transcriptional system is activated in cancer may permit rational approaches to therapy based on this target. The phenomenon is probably linked to the drastic changes in protein homeostasis resulting of the accumulation of mutated proteins in cancer cells^105,97,106. Hsps have been known for a long time as being able to prevent protein aggregation by binding polypeptide clients destabilized during cellular stress, such as heat shock. HspB1 (Hsp27) but also HspB5 and HspB4, are the ATP-independent molecular chaperones that belong to the group of small Hsps characterized by a common alpha-crystallin domain in their C-terminal part as discussed above. Recently, small Hsps have been described to have an incredible number of crucial roles in normal unstressed cells as well as in pathological cells where they are usually expressed to high levels. These proteins are now considered as important therapeutic targets, particularly in cancer pathologies^107,108. Indeed, they display anti-apoptotic and tumorigenic properties and trigger host anti-cancer response inhibition, such as senescence^{109,110,111,112}. This results in aggressive cancer cell growth^113,114,115, metastasis formation and dissemination^116,117,118, and poor prognosis¹¹⁹.

Due to the deleterious resistance and enhanced aggressivity brought to cancer cells by Hsp27, a predicted high level of expression of this molecular chaperone usually results in poor clinical outcome in the case of gastric, uterine, breast, prostate, ovarian, kidney and head/neck cancers as well as in tumors from the urinary and nervous systems^98,120,119. Hsp27 is also deeply involved in the invasion of tumor cells into surrounding tissues and formation of metastatic colonies^116,117,121.  Moreover, high levels of Hsp27 expression affect tumor susceptibility to adjuvant cancer treatments, including chemotherapy, hyperthermia and radiation therapies. Many client proteins are targeted by Hsp27 to promote resistance to cell death and malignant phenotype^122,123,119. Of particular interest, elevated levels of Hsp27 have also been detected in several cancer stem cells, such as those from lung and breast cancers^99,124. In these cells, Hsp27 participates in their maintenance since its elimination suppresses epithelial-mesenchymal transition (EMT) signatures linked to snail, vimentin, E-cadherin and NF-κB¹²⁴ and induces long-term dormancy¹²⁵. Another worth noting point relates to Hsp27 ability to enhance cancer cells resistance to a large panel of anti-cancer drug. For example, in MCF-7 breast cancer cells exposed to doxorubicin, survival cells are those that overexpress Hsp27 consequently of the increased activity of the POU4F2/Brn-3b transcription factor¹²⁶. This factor, which is elevated in more than 60% of breast cancers, modifies growth and behavior of cancer cells by regulating the expression of several target genes. Hence, Hsp27 inhibition of drug-induced apoptosis by further enhancing Hsp27 expression also increases the cellular resistance to many anti-cancer drugs¹²⁷. Contradictory findings have also been reported. For example, in pancreatic cancer cells, Hsp27 has been linked with increased sensitivity¹²⁸ as well as with increased resistance¹²⁹ to gemcitabine. These differences are probably due to phosphorylation status of the Hsp27¹³⁰. While RNAi strategies aimed at therapeutically decrease Hsp27 level as well as the search for inhibiting drugs are nowadays deeply active, the use of Hsp27 in the clinic is still mainly as a prognostic indicator of specific cancer types^131,132.