Selective inhibitory effects of zinc on cell proliferation in esophageal squamous cell carcinoma through Orai1

被引:73
作者
Choi, Sangyong [1 ,2 ]
Cui, Chaochu [1 ,2 ,4 ]
Luo, Yanhong [2 ,5 ]
Kim, Sun-Hee [2 ]
Ko, Jae-Kyun [6 ]
Huo, Xiaofang [7 ,8 ]
Ma, Jianjie [2 ,3 ]
Fu, Li-Wu [4 ]
Souza, Rhonda F. [7 ,8 ]
Korichneva, Irina [9 ]
Pan, Zui [1 ,2 ]
机构
[1] Univ Texas Arlington, Coll Nursing & Hlth Innovat, 501 S Nedderman Dr,Life Sci Bldg 241, Arlington, TX 76019 USA
[2] Ohio State Univ, Davis Heart & Lung Res Inst, Wexner Med Ctr, Columbus, OH 43210 USA
[3] Ohio State Univ, Dept Surg, Wexner Med Ctr, Columbus, OH 43210 USA
[4] Sun Yat Sen Univ, Collaborat Innovat Ctr Canc Med, State Key Lab Oncol South China, Canc Ctr, Guangzhou, Guangdong, Peoples R China
[5] Chongqing Med Univ, Dept Endocrinol, Childrens Hosp, Chongqing, Peoples R China
[6] Mutagenex, Suwanee, GA USA
[7] Baylor Univ, Med Ctr, Ctr Esophageal Dis, Dallas, TX USA
[8] Baylor Scott & White Res Inst, Ctr Esophageal Res, Dallas, TX USA
[9] Univ Picardie Jules Verne, Dept Pharmacol, Amiens, France
基金
美国国家卫生研究院;
关键词
intracellular Ca2+ oscillations; cancer prevention; histidine; redox sensor; INTRACELLULAR CA2+; CRAC CHANNELS; ION CHANNELS; CANCER; RECEPTOR; PERMEATION; EXPRESSION; BINDING; DOMAIN; DAMAGE;
D O I
10.1096/fj.201700227RRR
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
Zinc, an essential micronutrient, has a cancer preventive role. Zinc deficiency has been shown to contribute to the progression of esophageal cancer. Orai1, a store-operated Ca2+ entry (SOCE) channel, was previously reported to be highly expressed in tumor tissues removed from patients with esophageal squamous cell carcinoma (ESCC) with poor prognosis, and elevation of its expression contributes to both hyperactive intracellular Ca2+ oscillations and fast cell proliferation in human ESCC cells. However, the molecular basis of cancer preventive functions of zinc and its association with Orai1-mediated cell proliferation remains unknown. The present study shows that zinc supplementation significantly inhibits proliferation of ESCC cell lines and that the effect of zinc is reversible with N,N,N', N'-tetrakis (2-pyridylmethyl) ethylenediamine, a specific Zn2+ chelator, whereas non-tumorigenic esophageal epithelial cells are significantly less sensitive to zinc treatment. Fluorescence live cell imaging revealed that extracellular Zn2+ exerted rapid inhibitory effects on Orai1-mediated SOCE and on intracellular Ca2+ oscillations in the ESCC cells. Knockdown of Orai1 or expression of Orai1 mutants with compromised zinc binding significantly diminished sensitivity of the cancer cells to zinc treatment in both SOCE and cell proliferation analyses. These data suggest that zinc may inhibit cell proliferation of esophageal cancer cells through Orai1-mediated intracellular Ca2+ oscillations and reveal a possible molecular basis for zinc-induced cancer prevention and Orai1-SOCE signaling pathway in cancer cells.
引用
收藏
页码:404 / +
页数:17
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