Hsp27 is expressed in response to a wide variety of physiological and environmental insults including anticancer chemotherapy, allowing tumor cells to survive lethal conditions.
Several mechanisms are thought to account for the cytoprotective effect of Hsp27:
In cancer cells, the expression of Hsp27 is abnormally high, and Hsp27 may participate in oncogenesis and in chemoresistance
In rodent models, Hsp27 over-expression increases tumor growth and metastatic potential.
The depletion or inhibition of Hsp27 frequently reduces the size of tumors and can even cause their complete regression.
These observations have led to Hsp27 becoming a novel target in cancer biology and it’s inhibition a new strategy in the development of innovative therapeutics like RP101.
Chemoresistance: Hsp27 is expressed in response to anticancer chemotherapy, Hsp27 is thought to participate in oncogenesis and in resistance to chemotherapy.
e.g. Increased Hsp27 expression is related to higher rates of gemcitabine resistance in patients with pancreatic cancer.
Multi drug resistance: Hsp27 is linked to multi drug resistance (MDR) in human hepatic cancer cells.
Reactive oxygen species resistance: Hsp27 accumulation, probably due to its ability to decrease reactive oxygen species (ROS) levels, is essential for the development of resistance.
Influence on oncogenes: In prostate cancer Hsp27 interacts with the oncogene Stat3. These findings have identified Hsp27 as a potential therapeutic target in advanced prostate cancer.
DNA-repair: Enzymes of DNA base excision repair are associated with Hsp27.
Genetic recombination: DNA topoisomerases are involved in several aspects of DNA metabolism, in particular genetic recombination. The apoptotic protective effect of Hsp27 overexpression is associated with altered topoisomerase II expression.
Gene amplification: Abnormal amplification/expression of HER-2/neu oncogene has been causally linked with tumorigenesis and metastasis in breast cancer. A significant correlation between phosphorylated Hsp27, HER-2/neu status and lymph node positivity in breast cancer has recently been described.
Apoptosis: Hsp27 inhibits cytochrome c induced apoptosis and
binding of caspase-3 prodomain to Hsp27 also regulates apoptosis.
Immune response: Infiltrations of natural killer (NK) cells may have internal correlation with the expression of Hsp27. Moreover, Hsp27 protects cells from monocyte cytotoxicity.
Metastasis: In cancer patients high levels of hsp27 are associated with metastatic tissues compared to non metastatic tissues suggesting that it plays a key role in metastases formation.
In addition to the known effects of Hsp27, it is important to recognize that Hsp27 over expression has been detected in a wide range of different tumors, reinforcing it as an important target in tumor biology.
In pancreatic cancer cells, the expression of Hsp27 is abnormally high:
The figure shows the ROC curve for Hsp27 serum concentration for patients with pancreatic carcinoma and controls.
According to Melle et al. (2007), Clin. Chem., 2007; 53: 629 - 635.
HSP27
