The Keap1–Nrf2 pathway: promising therapeutic target to counteract ROS-mediated damage in cancers and neurodegenerative diseases

被引:290
作者
Deshmukh P. [1 ]
Unni S. [1 ]
Krishnappa G. [1 ]
Padmanabhan B. [1 ]
机构
[1] Department of Biophysics, National Institute of Mental Health and Neurosciences (NIMHANS), Hosur Road, Bangalore
关键词
Cancer; Inhibitors; Keap1; Neurodegenerative disorders; Nrf2; Oxidative stress;
D O I
10.1007/s12551-016-0244-4
中图分类号
学科分类号
摘要
The overproduction of reactive oxygen species (ROS) generates oxidative stress in cells. Oxidative stress results in various pathophysiological conditions, especially cancers and neurodegenerative diseases (NDD). The Keap1–Nrf2 [Kelch-like ECH-associated protein 1–nuclear factor (erythroid-derived 2)-like 2] regulatory pathway plays a central role in protecting cells against oxidative and xenobiotic stresses. The Nrf2 transcription factor activates the transcription of several cytoprotective genes that have been implicated in protection from cancer and NDD. The Keap1–Nrf2 system acts as a double-edged sword: Nrf2 activity protects cells and makes the cell resistant to oxidative and electrophilic stresses, whereas elevated Nrf2 activity helps in cancer cell survival and proliferation. Several groups in the recent past, from both academics and industry, have reported the potential role of Nrf2-mediated transcription to protect from cancer and NDD, resulting from mechanisms involving xenobiotic and oxidative stress. It suggests that the Keap1–Nrf2 system is a potential therapeutic target to combat cancer and NDD by designing and developing modulators (inhibitors/activators) for Nrf2 activation. Herein, we review and discuss the recent advancement in the regulation of the Keap1–Nrf2 system, its role under physiological and pathophysiological conditions including cancer and NDD, and modulators design strategies for Nrf2 activation. © 2016, International Union for Pure and Applied Biophysics (IUPAB) and Springer-Verlag Berlin Heidelberg.
引用
收藏
页码:41 / 56
页数:15
相关论文
共 130 条
[1]  
Adam J., Hatipoglu E., O'Flaherty L., Ternette N., Sahgal N., Lockstone H., Baban D., Nye E., Stamp G.W., Wolhuter K., Stevens M., Renal cyst formation in Fh1-deficient mice is independent of the Hif/Phd pathway: roles for fumarate in Keap1 succination and Nrf2 signaling, Cancer Cell, 20, 4, pp. 524-537, (2011)
[2]  
Adibhatla R.M., Hatcher J.F., Lipid oxidation and peroxidation in CNS health and disease: from molecular mechanisms to therapeutic opportunities, Antioxid Redox Signal, 12, 1, pp. 125-169, (2010)
[3]  
Albin R.L., Reiner A., Anderson K.D., Dure L.S., Handelin B., Balfour R., Whetsell W.O., Penney J.B., Young A.B., Preferential loss of striato-external pallidal projection neurons in presymptomatic Huntington’s disease, Ann Neurol, 31, 4, pp. 425-430, (1992)
[4]  
Albrecht P., Bouchachia I., Goebels N., Henke N., Hofstetter H.H., Issberner A., Kovacs Z., Lewerenz J., Lisak D., Maher P., Mausberg A.K., Effects of dimethyl fumarate on neuroprotection and immunomodulation, J Neuroinflammation, 9, 163, pp. 2094-2099, (2012)
[5]  
Ariga H., Takahashi-Niki K., Kato I., Maita H., Niki T., Iguchi-Ariga S.M., Neuroprotective function of DJ-1 in Parkinson’s disease, Oxidative Med Cell Longev, (2013)
[6]  
Aronowski J., Zhao X., Molecular pathophysiology of cerebral hemorrhage: secondary brain injury, Stroke, 42, 6, pp. 1781-1786, (2011)
[7]  
Arrasate M., Mitra S., Schweitzer E.S., Segal M.R., Finkbeiner S., Inclusion body formation reduces levels of mutant huntingtin and the risk of neuronal death, Nature, 431, 7010, pp. 805-810, (2004)
[8]  
Bae S.H., Sung S.H., Oh S.Y., Lim J.M., Lee S.K., Park Y.N., Lee H.E., Kang D., Rhee S.G., Sestrins activate Nrf2 by promoting p62-dependent autophagic degradation of Keap1 and prevent oxidative liver damage, Cell Metab, 17, 1, pp. 73-84, (2013)
[9]  
Behl C., Oxidative stress in Alzheimer’s disease: implications for prevention and therapy, pp. 65-78, (2005)
[10]  
Bouillez A., Rajabi H., Pitroda S., Jin C., Alam M., Kharbanda A., Tagde A., Wong K.K., Kufe D., Inhibition of MUC1-C suppresses MYC expression and attenuates malignant growth in KRAS mutant lung adenocarcinomas, Cancer Res, 76, 6, pp. 1538-1548, (2016)