INTRODUCTION
Stressful conditions trigger certain defence mechanisms, including those at molecular levels. This was first seen in Drosophilia and was reported in 1974.1 Heat Shock Proteins (HSPs), also known as Stress-induced Proteins or Stress Proteins, are one such class of proteins that are produced in the body in response to stress, under the control of Heat Shock Factors (HSFs), although some are constitutively expressed. The stress may be heat, cold, UV radiation, infections, inflammation, heavy metal exposure or else. HSPs are produced by all organisms and are ubiquitously present. The primary involvement of these proteins is in the folding and stabilization of other proteins, and thus they play an intimate role in the
aggregation of various other proteins.2 Besides action on protein folding, these HSPs also possess pro- and anti-apoptotic properties, making them suitable targets for drug development. The HSP families are classified according to their molecular weight.3 Table 1 describes in brief the classification as well as a few functions of these proteins.
In the recent past, various drug have been developed which act in line or against the HSPs but a still in their infancy. Besides drugs, the HSPs are also employed as diagnostic tools in various cancers. These are referenced in Table 2.
The flip side is the new set of adverse effects which are seen with these class of drugs. In patients with H.pylori infection which is implicated in the development of gastric carcinoma, it was observed that HSPs contributed to the progression of H. pylori-associated gastric carcinogenesis as well as led to the aggravation of gastric inflammation.33
Table 1: Functions of Heat Shock Proteins
| Family | Function |
| HSP90
(constitutive, induced)4 – 8 |
– Regulatory interactions with signalling proteins
– Protein synthesis, folding and degradation – Stabilization of misfolded proteins – Binding of estrogen, progesterone, androgen, and aldosterone 5 – Delivery of antigens to APCs 6 – Cancer cells: enhances growth, supresses senescence, provides resistance to stress induced apoptosis. 7 – Cardioprotective: binds to NO synthase and Guanylate cyclase, cause vascular relaxation 8 |
| HSP70
(constitutive) 6, 9 – 12 |
– Protein folding, membrane transport of proteins 9
– Anti-apoptotic 10 – Delivery of antigens to APCs 6 – In sympathetic neurons: 11 • HSP 72 – inhibits degradation of Tau protein, heat shock inducible • HSC 70 – promotes degradation of Tau protein Low levels – associated with insulin resistance 12 |
| HSP60
(constitutive) |
– In the mitochondria, replication and transcription of DNA, pro-survival. 13
– In the cytosol, complexes and inhibits maturation and activation of Caspase 3 – Anti apoptotic 14 – At the surface and extracellularly, stimulates immune response 15 |
| HSP40 | – Protein folding, co-chaperon for HSP70 16
– HSP40-70 complex – modulate accumulation of polyglutamine proteins 17 |
| HSP27 (β1) (induced) | – Anti-apoptotic, prevents proteolysis by inhibiting liberation of cytochrome c from mitochondria18 |
| Small HSPs | – Stabilization of misfolded proteins19 |
Table 2: Drugs acting via HSPs
| Family | Drug | Disease |
| Against HSP90 | Geldanamycin
(derivative, 17-allylamine,17-demethoxigeldanamycin) |
Malaria20
Huntington’s disease21 Cacncers22,23 |
| Efungumab | Invasive Candidiasis24 |
| Against HSP70 | Triptolide | Pancreatic cancer25
Mesothelioma26 |
| Methylene blue (inhibits ATPase activity of HSP72) | Alzheimer’s disease27 | |
| Pro-HSP60 | Bortezomib28 | Malignancies, increases expression of HSP60 on malignant cells and thus enhances immune response against tumour cells |
| Against HSP40 | Quercetin (inhibits HSP 40 and 27) | Parkinson’s disease29
Cancer30 |
| Against HSP27 | Apatorsen (antisense oligonucleotide) | Cancer31 |
| Diagnostic tool32 | Increased levels – Renal injury and fibrosis, Cancers of breast, lung, liver, prostate, rectal, osteosarcoma, leukaemia, cerebral and cardiac ischemia | |
| Reduced levels – oesophageal cancer | ||
| Anti-HSP27 IgA – Gynaecological malignancies |
|
Autoimmune disease: Since these are highly conserved in nature, they are the initiators as well as the targets of autoimmune attack. Molecular mimicry and cross presentation of antigens are the phenomena of their involvement in autoimmunity. Their roles have been implicated in atherosclerosis, uveitis, lupus and Behcet’s disease. 34
Atherosclerosis: Risk factors for atherosclerosis including infection, oxidative stress, biomechanical stress, all lead to the overproduction of HSPs through the activation of heat shock transcription factor 1 which may lead to worsening of atherosclerosis.35
The anti-apoptotic property may lead to a poor prognosis and resistance to therapy in cancer which the anti-apoptotic activity may be therapeutically advantageous.36
Insomnia or sleep deprivation can lead to an increased level of HSPs acting as a neuroprotective response, emphasizing on the role of adequate sleep in disease prevention.37
CONCLUSION
Harms and benefits are two sides of the same coin, as is the case with heat shock proteins. Despite their presence ubiquitously, a small rise or fall in their levels can have a different specific new set of adverse implications. However, despite the availability of information, further research in needed in order to develop newer drugs which may prove beneficial in the treatment of difficult, incurable diseases.
REFERENCES
- Schlesinger, M. J. (1990). Heat shock proteins. The Journal of Biological Chemistry, 265(21), 12111–12114. PMid:2197269
- Lindquist, S., & Craig, E. A. (1988). The heat-shock proteins. Annual review of
genetics, 22(1), 631-677. https://doi.org/10.1146/annurev.ge.22.120188.003215, PMid:2853609
- Wirth, D., Gustin, P., Drion, P., Dessy-Doize, C., & Christians, E. S. (2002). Heat shock proteins. I: Classification and roles in pathological processes. In Annales de Médecine Vétérinaire (Vol. 146, No. 4, pp. 201-216). Annales Medecine Veterinaire.
- Jackson, S. E. (2012). Hsp90: structure and function. In Molecular chaperones(pp. 155-240). Springer, Berlin, Heidelberg. https://doi.org/10.1007/128_2012_356,
PMid:22955504 - Joab, I., Radanyi, C., Renoir, M., Buchou, T., Catelli, M. G., Binart, N., … & Baulieu, E. E. (1984). Common non-hormone binding component in non-transformed chick oviduct receptors of four steroid hormones. Nature, 308(5962), 850. https://doi.org/10.1038/308850a0,
PMid:6201744 - Gaston, J. S. H. (2002). Heat Shock Proteins and Innate immunity. Clin Exp Immunol, 127(1), 1–3. https://doi.org/10.1046/j.1365-2249.2002.01759.x,
https://doi.org/10.1111/j.1365-2249.1990.tb05394.x, PMid:11882025, PMCid:PMC1906278 - Workman, P., Burrows, F., Neckers, L., & Rosen, N. (2007). Drugging the cancer chaperone HSP90: combinatorial therapeutic exploitation of oncogene addiction and tumor stress. Ann N Y Acad Sci, 1113, 202–216. https://doi.org/10.1196/annals.1391.012,
PMid:17513464 - Antonova, G., Lichtenbeld, H., Xia, T., Chatterjee, A., Dimitropoulou, C., & Catravas J. D. (2007). Functional significance of hsp90 complexes with NOS and sGC in endothelial cells. Clin Hemorheol Microcirc, 37(1-2), 19-35.
- Hartl, F.U. (1996). Molecular chaperones in cellular protein folding. Nature, 381, 571-579. https://doi.org/10.1038/381571a0,
PMid:8637592 - Gehrmann, M., Radons, J., Molls, M., & Multhoff, G. (2008). The therapeutic implications of clinically applied modifiers of heat shock protein 70 (Hsp70) expression by tumor cells. Cell Stress Chaperones, 13(1), 1-10. https://doi.org/10.1007/s12192-007-0006-0, PMid:18347936, PMCid:PMC2666213
- Jinwal, U. K., Akoury, E., Abisambra, J. F., O’Leary, J. C., Thompson, A.D., Blair, L. J., et al. (2013). Imbalance of Hsp70 family variants fosters tau accumulation. FASEB J, 27(4), 1450-1459. https://doi.org/10.1096/fj.12-220889, PMid:23271055, PMCid:PMC3606536
- Chichester, L., Wylie, A. T., Craft, S., & Kavanagh, K. (2015). Muscle heat shock protein 70 predicts insulin resistance with aging. J Gerontol A Biol Sci Med Sci, 70(2), 155-62. https://doi.org/10.1093/gerona/glu015,
PMid:24532784, PMCid:PMC4311181 - Kaufman, B. A., Kolesar, J. E., Perlman, P. S., & Butow, R. A. (2003). A function for the mitochondrial chaperonin Hsp60 in the structure and transmission of mitochondrial DNA nucleoids in Saccharomyces cerevisiae. J Cell Biol, 163, 457-461. https://doi.org/10.1083/jcb.200306132,
PMid:14597775, PMCid:PMC2173642 - Xanthoudakis, S., Roy, S., Rasper, D., Hennessey, T., Aubin, Y., Cassady, R., et al. (1999). Hsp60 accelerates the maturation of pro-caspase-3 by upstream activator proteases during apoptosis. EMBO J, 18(18), 2049-2056. https://doi.org/10.1093/emboj/18.8.2049,
PMid:10205159, PMCid:PMC1171289 - Pockley, A. G., Muthana, M., & Calderwood, S. K. (2008). The dual immunoregulatory roles of stress proteins. Trends Biochem Sci, 33, 71-79. https://doi.org/10.1016/j.tibs.2007.10.005,
PMid:18182297 - Castanie-Cornet, M. P., Bruel, N., & Genevaux, P. (2014). Chaperone networking facilitates protein targeting to the bacterial cytoplasmic membrane. Biochim Biophys. Acta, 1843, 1442-1456. https://doi.org/10.1016/j.bbamcr.2013.11.007,
PMid:24269840 - Wacker, J. L., Zareie, M. H., Fong, H., Sarikaya, M., & Muchowski, P. J. (2004). Hsp70 and Hsp40 attenuate formation of spherical and annular polyglutamine oligomers by partitioning monomer. Nature Structural & Molecular Biology, 11(12), 1215-1222. https://doi.org/10.1038/nsmb860,
PMid:15543156 - Paul, C., Manero, F., Gonin, S., Kretz-Remy, C., Virot, S., & Arrigo, A. P. (2002). Hsp27 as a negative regulator of cytochrome C release. Mol Cell Biol, 22(3):816-34. https://doi.org/10.1128/MCB.22.3.816-834.2002, PMid:11784858, PMCid:PMC133538
- Ungelenk, S., Moayed, F., Ho, C. T., Grousl, T., Scharf, A., Mashaghi, A., et al. (2016). Small heat shock proteins sequester misfolding proteins in near-native conformation for cellular protection and efficient refolding. Nature Communications, 7, Article number: 13673. https://doi.org/10.1038/ncomms13673,
PMid:27901028, PMCid:PMC5141385 - Wang, T., Maser, P., & Picard, D. (2016). Inhibition of Plasmodium falciparum Hsp90 Contributes to the Antimalarial Activities of Aminoalcohol-carbazoles. Med. Chem., 59(13), 6344–6352. https://doi.org/10.1021/acs.jmedchem.6b00591, PMid:27312008
- Sittler, A., Lurz, R., Lueder, G., Priller, J., Lehrach, H., Hayer-Hartl, M. K., et al. (2001). Geldanamycin activates a heat shock response and inhibits huntingtin aggregation in a cell culture model of Huntington’s disease. Human Molecular Genetics, 10(12), 1307-1315. https://doi.org/10.1093/hmg/10.12.1307,
PMid:11406612 - Jurczyszyn, A., Zebzda, A., Czepiel, J., Perucki, W., Bazan-Socha, S., Cibor, D., et al. (2014). Geldanamycin and Its Derivatives Inhibit the Growth of Myeloma Cells and Reduce the Expression of the MET Receptor. J Cancer, 5(6), 480–490. https://doi.org/10.7150/jca.8731, PMid:24959301, PMCid:PMC4066360
- Li, Y., Zhang, T., & Sun, D. (2009). New developments in Hsp90 inhibitors as anti-cancer therapeutics: mechanisms, clinical perspective and more potential. Drug Resist Updat, 12(1-2), 17–27. https://doi.org/10.1016/j.drup.2008.12.002,
PMid:19179103, PMCid:PMC2692088 - Karwa, R., & Wargo, K. A. (2009). Efungumab: a novel agent in the treatment of invasive candidiasis. Ann Pharmacother, 43(11), 1818-1823. https://doi.org/10.1345/aph.1M218,
PMid:19773528 - Phillips, P. A., Dudeja, V., McCarroll, J.A., Borja-Cacho, D., Dawra, R. K., Grizzle, W. E., et al. (2007). Triptolide induces pancreatic cancer cell death via inhibition of heat shock protein 70. Cancer Res, 67(19), 9407-9416. https://doi.org/10.1158/0008-5472.CAN-07-1077, PMid:17909050
- Jacobson, B. A., Chen, E. Z., Tang, S., Belgum, H. S., McCauley, J. A., Evenson, K. A., et al. (2015). Triptolide and its prodrug minnelide suppress Hsp70 and inhibit in vivo growth in a xenograft model of mesothelioma. Genes Cancer, 6(3-4), 144–152. PMid:26000097, PMCid:PMC4426951
- O’Leary, J. C., Li, Q., Marinec, P., Blair, L. J., Congdon, E. E., Johnson, A. G., et al. (2010). Phenothiazine-mediated rescue of cognition in tau transgenic mice requires neuroprotection and reduced soluble tau burden. Molecular Neurodegeneration, 5(1), Article 45. https://doi.org/10.1186/1750-1326-5-45,
PMid:21040568, PMCid:PMC2989315 - Chang, C. L., Hsu, Y. T., Wu. C. C., Yang, Y. C., Wang, C., Wu, T. C., et al. (2012). Immune mechanism of the antitumor effects generated by bortezomib. J Immunol, 189(6), 3209-3220. https://doi.org/10.4049/jimmunol.1103826,
PMid:22896634 - Ekimov, I. V., & Plaksina, D. V. (2017). Effects of Quercetin on Neurodegenerative and Compensatory Processes in the Nigrostriatal System in a Model of the Preclinical Stage of Parkinson’s Disease in Rats. Neuroscience and Behavioral Physiology, 47(9), 1029–1036. https://doi.org/10.1007/s11055-017-0508-x
- McConnell, J. R., & McAlpine, S. R. (2013). Heat shock proteins 27, 40, and 70 as combinational and dual therapeutic cancer targets. Bioorg Med Chem Lett, 23(7), 1923–1928. https://doi.org/10.1016/j.bmcl.2013.02.014,
PMid:23453837, PMCid:PMC3602338 - Chi, K. N., Yu, E. Y., Jacobs, C., Bazov, J., Kollmannsberger, C., Higano, C.S., et al. (2016). A phase I dose-escalation study of apatorsen (OGX-427), an antisense inhibitor targeting heat shock protein 27 (Hsp27), in patients with castration-resistant prostate cancer and other advanced cancers. Ann Oncol, 27(6), 1116-1122. https://doi.org/10.1093/annonc/mdw068,
PMid:27022067 - Vidyasagar, A., Wilson, N. A., & Djamali, A. (2012). Heat shock protein 27 (HSP27): biomarker of disease and therapeutic target. Fibrogenesis & Tissue Repair, 5(1), 7. https://doi.org/10.1186/1755-1536-5-7,
PMid:22564335, PMCid:PMC3464729 - Lee, H. J., Ock, C.Y., Kin, S. J., & Hahm, K. B. (2010). Heat Shock Protein: Hard Worker or Bad Offender for Gastric Diseases. International Journal of Proteomics, 2010, 1-11. https://doi.org/10.1155/2010/259163,
PMid:22084675, PMCid:PMC3195352 - Moudgil, K. D., Thompson, S. J., Geraci, F., Paepe, B. D., & Shoenfeld, Y. (2013). Heat-Shock Proteins in Autoimmunity. Autoimmune Diseases, 2013; 1-3. https://doi.org/10.1155/2013/621417
- Xu, Q. (2002). Role of Heat Shock Proteins in Atherosclerosis. Atherosclerosis, Thrombosis and Vascular biology, 22, 1547-1559. https://doi.org/10.1161/01.ATV.0000029720.59649.50
- Calderwood, S.K., & Gong, J. (2016). Heat Shock Proteins Promote Cancer: It’s a Protection Racket. Trends in Biochemical Sciences, 41(4), 311-323. https://doi.org/10.1016/j.tibs.2016.01.003,
PMid:26874923, PMCid:PMC4911230 - Terao, A., Steininger, T. L., Hyder, K., Apte-Deshpande, A., Ding, J., Rishipathak, D., et al. (2003). Differential increase in the expression of heat shock protein family members during sleep deprivation and during sleep. Neuroscience, 116(1), 187-200. https://doi.org/10.1016/S0306-4522(02)00695-4
