铜转运蛋白与癌症的研究进展
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摘要
铜是所有生物体中必不可少的一类具有氧化还原性质的过渡金属,也是催化抗氧化、铁稳态、细胞呼吸和各种生化过程关键酶的辅助因子.但是,由于其潜在的毒副作用,细胞内游离的铜离子必须受到严格的调控.铜离子平衡的失调会导致包括癌症和神经退行性疾病的发生和发展.例如,铜离子的积累可能会导致氧化应激的增加以及与大分子非特异性地结合.因此,大多数细胞进化出复杂的铜调节和转运系统,以满足细胞对铜离子的需求,同时减少其潜在的毒性.本文详细介绍了铜转运蛋白Ctr1、铜伴侣蛋白CCS、Atox1、COX17对于维持细胞内铜离子平衡的重要意义,同时着重介绍了铜伴侣蛋白在肿瘤中的研究进展以及相关药物的发展,为铜紊乱疾病治疗新靶点的发现和药物的研发提供了理论基础.
Copper is a redox-active transition metal essential for most living organisms and serves as a catalytic cofactor for enzymes that function in antioxidant defence, iron homeostasis, cellular respiration and a variety of biochemical processes. However, intracellular free copper must be strictly limited because of its potential toxic side effects. Copper dyshomeostasis is involved in the pathogenesis and progression of diseases including cancer and neurodegenerative diseases. The uncontrolled accumulation of copper could lead to increased oxidative stress and inappropriate binding to macromolecules. Most cells evolve complex systems of copper regulation and trafficking to satisfy the cellular copper requirements and simultaneously minimize the potential toxicity. This review presents the importance of copper transporter Ctr1, copper chaperone CCS, Atox1 and COX17 for the maintenance of copper ion balance in cells.Moreover, we discuss recent highlights in the development of copper chelators for the treatment of cancer. Finally, we introduce the development of small molecules that alter copper homeostasis by inhibiting copper chaperones.
Copper is a redox-active transition metal essential for most living organisms and serves as a catalytic cofactor for enzymes that function in antioxidant defence, iron homeostasis, cellular respiration and a variety of biochemical processes. However, intracellular free copper must be strictly limited because of its potential toxic side effects. Copper dyshomeostasis is involved in the pathogenesis and progression of diseases including cancer and neurodegenerative diseases. The uncontrolled accumulation of copper could lead to increased oxidative stress and inappropriate binding to macromolecules. Most cells evolve complex systems of copper regulation and trafficking to satisfy the cellular copper requirements and simultaneously minimize the potential toxicity. This review presents the importance of copper transporter Ctr1, copper chaperone CCS, Atox1 and COX17 for the maintenance of copper ion balance in cells.Moreover, we discuss recent highlights in the development of copper chelators for the treatment of cancer. Finally, we introduce the development of small molecules that alter copper homeostasis by inhibiting copper chaperones.
引文
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2 Inesi G.IUBMB Life,2016,69:211-217
3 Lutsenko S,Bhattacharjee A,Hubbard AL.Metallomics,2010,2:596-608
4 Scheinberg IH,Sternlieb I.Am J Clin Nutrit,1996,63:842S-845S
5 Zhong L,Wang L,Xu L,Liu Q,Jiang L,Zhi Y,Lu W,Zhou P.Biometals,2015,28:113-122
6 Hordyjewska A,Popio?ek?,Kocot J.Biometals,2014,27:611-621
7 Robinson NJ,Winge DR.Annu Rev Biochem,2010,79:537-562
8 La Fontaine S,Mercer JFB.Archiv Biochem Biophys,2007,463:149-167
9 Waldron KJ,Rutherford JC,Ford D,Robinson NJ.Nature,2009,460:823-830
10 Puig S,Thiele DJ.Curr Opin Chem Biol,2002,6:171-180
11 Maryon EB,Molloy SA,Zimnicka AM,Kaplan JH.Biometals,2007,20:355-364
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13 De Feo CJ,Aller SG,Siluvai GS,Blackburn NJ,Unger VM.Proc Natl Acad Sci USA,2009,106:4237-4242
14 Kahra D,Kovermann M,Wittung-Stafshede P.Biophys J,2016,110:95-102
15 Puig S,Lee J,Lau M,Thiele DJ.J Biol Chem,2002,277:26021-26030
16 Maryon EB,Molloy SA,Kaplan JH.Am J Phys-Cell Phys,2013,304:C768-C779
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