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Current Cancer Drug Targets

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ISSN (Print): 1568-0096
ISSN (Online): 1873-5576

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Research Article

Arsenic Trioxide Restrains Lung Cancer Growth and Metastasis by Blocking the Calcineurin-NFAT Pathway by Upregulating DSCR1

Author(s): Meng-Hang Yang*, Yu-Sheng Wang, Xiao-Qian Shi, Xue-Wei Zhao* and Bing Li*

Volume 22, Issue 10, 2022

Published on: 18 August, 2022

Page: [854 - 864] Pages: 11

DOI: 10.2174/1568009622666220629154619

Price: $65

Abstract

Background: Anti-angiogenesis therapy mostly aimed at targeting vascular endothelial growth factor (VEGF) and its receptors have been widely applied to lung cancer. However, the improvement in the patient's overall survival remains dissatisfying. Previously, we demonstrated that arsenic trioxide (As2O3) exerts an anti-lung cancer effect through anti-angiogenesis, but the details of the mechanism in play remain unclear. Herein, we focused on the calcineurin-NFAT pathway, downstream of VEGF, and its endogenous inhibitor DSCR1.

Objective: To demonstrate the mechanism of As2O3 restraining lung cancer growth and metastasis by blocking the calcineurin-NFAT pathway by upregulating DSCR1.

Methods: We constructed xenografts and metastasis models based on wild-type (WT) and DSCR1 knockout (DSCR1-/-) mice, and carried out qPCR, Western blot, immunohistochemistry, in vivo imaging and calculated microvessel density to evaluate the effects of As2O3 on angiogenesis, tumor growth, metastasis, and the protein expression levels of DSCR1 and calcineurin-NFAT pathway-related molecules.

Results: As2O3 inhibited tumor growth and metastasis, reduced microvessel formation, and induced vascular lumen malformation in WT mice. At the protein level, As2O3 upregulated DSCR1, downregulated NFAT2 and its downstream molecules, but had no effect on calcineurin A. However, in DSCR1-/- mice, the above-mentioned effects of As2O3 were abolished.

Conclusion: As2O3 can suppress lung cancer growth and metastasis through anti-angiogenesis effects by blocking the calcineurin-NFAT pathway by upregulating DSCR1. The results shed light on the antitumor mechanism of As2O3 and are a step forward in the identification of As2O3 as a new drug in the treatment of lung cancer.

Keywords: Arsenic trioxide, lung cancer, angiogenesis, metastasis, calcineurin-NFAT, DSCR1.

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