HSP27: Disease Relevance

Hsp27 (HspB1) is involved in the generation of two big groups of diseases. The congenital diseases, due to mutations of the human HSPB family of proteins and degenerative diseases, like neurodegenerative disorders, cardiovascular pathologies and cancer. The first group is summarized on Table 3.

Hsp27 and Neurodegenerative Diseases
Many neurodegenerative disorders are accompanied by accumulation of insoluble protein aggregates or amyloid fibrils in neurons or glia cells. Trying to avoid accumulation of protein aggregates, the cell increases expression of Hsp27. In neurons of patients with Alzheimer’s and Parkinson’s disease, Hsp27 is colocalized with Lewy’s bodies^77,78, neurofibrillar tangles⁷⁹, and senile plaques formed by β-amyloid^80,81. Hsp27 is able to prevent α-sinuclein aggregation in the culture of neurons overexpressing α-sinuclein and thus increases neuron survival^78,79. Increased expression of Hsp27 in the case of dementia with Lewy’s bodies is probably one of the ways for decreasing cytotoxicity induced by misfolded and aggregated α-synuclein⁷⁸. Hsp27 interacts with hyperphosphorylated tau proteins that form neurofibrillar tangles in neurons of patients with Alzheimer’s disease. Interaction with Hsp27 promotes tau dephosphorylation and induces proteasomal degradation of phosphorylated tau, probably by inducing changes in tau conformation⁸². Moreover, Hsp27 prevents apoptosis of neuronal cells induced by accumulation of hyperphosphorylated tau⁸². Although there is a large body of recent literature dealing with the role of Hsp27 on neurodegenerative diseases, a detailed molecular mechanisms underlying participation of Hsp27 in Alzheimer’s disease, amyotrophic lateral sclerosis, and Parkinson’s and Huntington’s diseases are still unknown. The main effect of Hsp27 in these disorders is probably due to its ability to prevent formation of amyloid fibrils and aggregates of denatured proteins. The main effect of Hsp27 in these disorders is probably due to its ability to prevent formation of amyloid fibrils and aggregates of misfolded proteins.

Hsp27 and Cardiovascular Diseases
Heart attack and stroke causes ischemia and reperfusion injury to cells and includes protein and enzyme denaturation, perturbation of oxidoreductive status, mitochondrial deterioration, cytoskeleton disruption and membrane lipid peroxidation⁸³. Five mammalian sHSPs, namely αB-crystallin (HspB5), MKBP (HspB2), Hsp25 (HspB1), Hsp20 (HspB6) and cv Hsp (HspB7) translocate from heart cell cytosol to myofibrils during ischemia, with varying localization to Z-lines, I-bands, and intercalated discs. Binding to microfibrils is tight and sHSPs may save stressed heart cells from harm by stabilizing sarcomeres⁸⁴.

Atherosclerosis is a chronic inflammatory process due to the endothelial reaction to stress risk factors. For instance, it has been observed that Hsp27 expression is decreased in complicated atherosclerotic plaques and that plasma Hsp27 levels are decreased in patients with atherosclerosis compared with healthy subjects. They suggested plasma Hsp27 levels could be a potential index of atherosclerosis, although further validation in large patient cohorts is required⁸⁵. In humans with cardiac allograft rejection, it has been suggested that increased expression of Hsp27, could be important for cardiac self-protection⁸⁶. Moreover, others have reported that during the development of heart failure, changes in the production of myocardial HSPS occurs⁸⁷. Despite an increase in the myocardial expression of Hsp27, which may bind to cytoskeletal elements of the cardiac myocytes, only the increase in myocardial Hsp60 production was associated with the development of heart failure. Diagnostic value of Hsp27 on cardiac patients still needs to be validated.

Hsp27 and Cancer
Heat shock proteins are over-expressed in a wide range of human cancers and are implicated in tumor cell proliferation, differentiation, invasion, metastasis, death and recognition by the immune system⁸⁸. Increased resistance of tumors to cancer therapy induced by Hsp27 over-expression seems to depend on many factors. As already mentioned, Hsp27 plays an important “housekeeping” role and protects the cell agaist different kinds of stresses (including chemotherapy) by preventing accumulation of aggregated proteins, modulating the redox state of the cell, protecting the cytoskeleton, modulating transcription, regulating apoptosis, and probably enhancing the DNA repair in cancer cells⁸⁹.

Defects in the apoptosis signaling pathways are common in cancer cells. Such defects may play a role in tumor initiation because apoptosis is the normal means by which cells with damaged DNA or dysregulated cell cycle, may be eliminated^82,20. Impaired apoptosis may also enhance tumor progression and promote metastasis by enabling tumor cells to survive the process of migration in the bloodstream and to grow in ectopic sites. It may also make the cells resistant to the various modalities of therapy. The use of siRNA for controlling the expression of Hsp27 in breast cancer have been seen to prevent the formation of lung metastasis in a breast cancer⁹⁰. Heat shock protein concentrations may be useful biomarkers for assessing the degree of differentiation and the aggressiveness of some cancers. Hsp27 expression is associated with poor prognosis in gastric, liver and prostate carcinoma, and osteosarcomas⁹¹. High Hsp27 expression also predicts a poor response to chemotherapy in breast cancer and leukemia, and may be related to estrogen in breast and to estrogen and progesterone in the endometrium. It has been shown that some but not all estrogen positive breast cancers express Hsp27 and its over-expression has been associated with the degree of tumor differentiation, and response to hormonal therapy like Tamoxifen. In endometrial carcinomas, the presence of Hsp27 is correlated with the degree of tumor differentiation as well as with the presence of estrogen and progesterone receptors. However, the detection of Hsp27 in endometrial carcinoma cannot be used to identify hormone-responsive tumors or indicator or presence of estradiol receptors. In the cervix Hsp27 is a marker of cell differentiation, and is highly expressed during the process of squamous metaplasia.
In Acute Lymphoblastic Leukemia (ALL), Hsp27 and its phosphorylated forms are over-expressed and may be used as related markers for it. Synthesis of Hsp27 is upregulated in gynecologic cancers and inhibits the induction of apoptosis. For instance, in ovarian and endometrial cancer, some women have presence of antibodies to the Hsp27 but not in women with non-malignant conditions or healthy women⁹². The appearance of these antibodies suggests that Hsp27 may be present in an extracellular form in gynecologic cancer patients. Cell-free Hsp27 and cytochrome c complexes can be detected in the lower genital tract of women with ovarian and endometrial cancers. Identification of these biomarkers may be beneficial in the early diagnosis of these malignancies, and circulating autoantibodies to the Hsp27 were associated with malignancies of the female genital tract.

The data presented correlate with the hypothesis that Hsp27 is an important regulator of proliferation and apoptosis and therefore may be of great importance in carcinogenesis. Expression of Hsp27 is significantly elevated in a number of tumors^89,93,94,95 and increased expression of Hsp27 usually correlates with increased resistance to cytotoxic (antineoplastic) compounds⁹⁶.

Table 3. The congenital diseases due to mutations of the human HSPB family of proteins

Name	Tissue Distribution	Disease
HspB1	Ubiquitous	Charcot-Marie-Tooth disease type 2, distal hereditary motor neuropathy
HspB2	Cardiac and skeletal muscle	Myotonic dystrophy, different forms neuropathology
HspB3	Cardiac and Skeletal muscle	Motor neuropathy
HspB4	Eye lens	Cataract
HspB5	Ubiquitous	Cataract
HspB6	Ubiquitous	Dilated cardiomyopathy
HspB8	Ubiquitous	Charcot-Marie-Tooth disease type 2, distal hereditary motor neuropathy
HspB9	Testis	Upregulated in certain tumors