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

Sangyong Choi, Chaochu Cui, Yanhong Luo, Sun Hee Kim, Jae Kyun Ko, Xiaofang Huo, Jianjie Ma, Li Wu Fu, Rhonda F. Souza, Irina Korichneva, Zui Pan

Research output: Contribution to journalArticle

9 Citations (Scopus)

Abstract

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,N9,N9-tetrakis (2-pyridylmethyl) ethylenediamine, a specific Zn2+ chelator, whereas nontumorigenic 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.

Original languageEnglish (US)
Pages (from-to)404-416
Number of pages13
JournalFASEB Journal
Volume32
Issue number1
DOIs
StatePublished - Jan 1 2018

Fingerprint

Cell proliferation
Zinc
Cell Proliferation
Cells
Neoplasms
ethylenediamine
Esophageal Neoplasms
Epithelial Cells
Esophageal Squamous Cell Carcinoma
Micronutrients
Chelating Agents
Tumors
Fluorescence
Tissue
Imaging techniques
Cell Line

Keywords

  • Cancer prevention
  • Histidine
  • Intracellular Ca2+ oscillations
  • Redox sensor

ASJC Scopus subject areas

  • Biotechnology
  • Biochemistry
  • Molecular Biology
  • Genetics

Cite this

Selective inhibitory effects of zinc on cell proliferation in esophageal squamous cell carcinoma through Orai1. / Choi, Sangyong; Cui, Chaochu; Luo, Yanhong; Kim, Sun Hee; Ko, Jae Kyun; Huo, Xiaofang; Ma, Jianjie; Fu, Li Wu; Souza, Rhonda F.; Korichneva, Irina; Pan, Zui.

In: FASEB Journal, Vol. 32, No. 1, 01.01.2018, p. 404-416.

Research output: Contribution to journalArticle

Choi, S, Cui, C, Luo, Y, Kim, SH, Ko, JK, Huo, X, Ma, J, Fu, LW, Souza, RF, Korichneva, I & Pan, Z 2018, 'Selective inhibitory effects of zinc on cell proliferation in esophageal squamous cell carcinoma through Orai1', FASEB Journal, vol. 32, no. 1, pp. 404-416. https://doi.org/10.1096/fj.201700227RRR
Choi, Sangyong ; Cui, Chaochu ; Luo, Yanhong ; Kim, Sun Hee ; Ko, Jae Kyun ; Huo, Xiaofang ; Ma, Jianjie ; Fu, Li Wu ; Souza, Rhonda F. ; Korichneva, Irina ; Pan, Zui. / Selective inhibitory effects of zinc on cell proliferation in esophageal squamous cell carcinoma through Orai1. In: FASEB Journal. 2018 ; Vol. 32, No. 1. pp. 404-416.
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AU - Ko, Jae Kyun

AU - Huo, Xiaofang

AU - Ma, Jianjie

AU - Fu, Li Wu

AU - Souza, Rhonda F.

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AB - 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,N9,N9-tetrakis (2-pyridylmethyl) ethylenediamine, a specific Zn2+ chelator, whereas nontumorigenic 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.

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