HSP27: Drug Discovery
Staining of somites of a rat embryo at 11 days of gestation. Red is rhodamine-phalloidin labeled actin and green is Hsp27, using Anti-Hsp27 (clone: 8A7)
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 systems98,120,119. Hsp27 is also deeply involved in the invasion of tumor cells into surrounding tissues and formation of metastatic colonies116,117,121. 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 phenotype122,123,119. Of particular interest, elevated levels of Hsp27 have also been detected in several cancer stem cells, such as those from lung and breast cancers99,124. 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 types131,132.