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NFATc3 mediates the sensitivity of gastric cancer cells to arsenic sulfide.

ABSTRACT: Arsenic sulfide (As₄S₄) is the main component of Realgar which is widely used in traditional Chinese medicine. Previously we showed that As₄S₄ inhibited the proliferation of colon cancer cells through regulating nuclear factor of activated T cells (NFAT) pathway. Here we explore the role of NFAT in gastric cancer. We showed that As₄S₄ inhibited the expression of NFATc1, NFATc3, and NFATc4, and modulated the expression of NFATc2 accompanying with p53. The baseline expression of NFATc3 varied distinctly in gastric cancer cell lines (AGS, MGC803, MKN28, MKN45, and SGC7901) and the sensitivity of these cells to As₄S₄ was dissimilar, with AGS and MGC803 cells showing higher sensitivity while the SGC7901 cells relatively resistant. Interestingly, the sensitivity to As₄S₄ was correlated with the level of expression of NFATc3, and the cells relatively sensitivity just showing higher expression of NFATc3. Furthermore, NFATc3 expression was significantly higher in gastric cancer tissues compared with the adjacent normal tissues. Our data also showed that, NFATc3 promoted the proliferation of gastric cancer cells by regulating c-Myc. In conclusion, As₄S₄ inhibited the proliferation of gastric cancer cells through NFATc3/c-Myc pathway and the diverse sensitivity among different cell lines correlated with the expression level of NFATc3 indicating that NFATc3 may be a potential therapeutic target in gastric cancer.

SUBMITTER: Zhang X

PROVIDER: S-EPMC5581065 | biostudies-literature | 2017 Aug

REPOSITORIES: biostudies-literature

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NFATc3 mediates the sensitivity of gastric cancer cells to arsenic sulfide.

Zhang Xiuli X Kang Ting T Zhang Lian L Tong Yingying Y Ding Wenping W Chen Siyu S

Oncotarget 20170418 32

Arsenic sulfide (As4S4) is the main component of Realgar which is widely used in traditional Chinese medicine. Previously we showed that As4S4 inhibited the proliferation of colon cancer cells through regulating nuclear factor of activated T cells (NFAT) pathway. Here we explore the role of NFAT in gastric cancer. We showed that As4S4 inhibited the expression of NFATc1, NFATc3, and NFATc4, and modulated the expression of NFATc2 ac ...[more]

PMID: 28881766

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Project description:BACKGROUND:Arsenic sulfide was found to have potential anti-cancer activities, especially in gastric cancer. However, the underlying mechanism need to be further explored. This study was aimed to investigate the mechanism of arsenic compounds on gastric cancer. METHODS:Gastric cancer cell lines were infected with lentiviral vector carrying shNFATc3 and/or treated with arsenic sulfide. MTT assay were performed to assess cell growth. Flow cytometer assays were used to detect cell cycle and reactive oxygen species (ROS) level of gastric cancer cells. Western blot was carried out to detect nuclear factor of activated T-cells, cytoplasmic 3 (NFATc3), cell cycle markers, DNA damage pathway protein expression as well as other protein expression in gastric cancer cell lines. The expression of recombination activating gene 1 (RAG1) in gastric cancer cell lines was determined by RNA-sequencing analyses and Real-Time qPCR. The effect of NFATc3 on RAG1 were determined by CHIP-qPCR assay. The effect of arsenic sulfide on AGS cells was evaluated in vivo. RESULTS:We show that arsenic sulfide as well as knockdown of NFATc3 resulted in increased double-strand DNA damage in gastric cancer cells by increasing the expression of RAG1, an endonuclease essential for immunoglobulin V(D) J recombination. Overexpression of NFATc3 blocked the expression of RAG1 expression and DNA damage induced by arsenic sulfide. Arsenic sulfide induced cellular oxidative stress to redistribute NFATc3, thereby inhibiting its transcriptional function, which can be reversed by N-acetyl-L-cysteine (NAC). We show that NFATc3 targets the promoter of RAG1 for transcriptional inhibition. We further showed that NFATc3 upregulation and RAG1 downregulation significantly associated with poor prognosis in patients with gastric cancer. Our in vivo experiments further confirmed that arsenic sulfide exerted cytotoxic activity against gastric cancer cells through inhibiting NFATc3 to activate RAG1 pathway. CONCLUSION:These results demonstrate that arsenic sulfide targets NFATc3 to induce double strand DNA break (DSB) for cell killing through activating RAG1 expression. Our results link arsenic compound to the regulation of DNA damage control and RAG1 expression as a mechanism for its cytotoxic effect.

Project description:We previously showed that arsenic sulfide (As4S4) induced cell cycle arrest and apoptosis in several human solid tumor cell lines, including those of gastric cancer. In this study, we investigated the effect of As4S4 on the migration and invasion of gastric cancer cells both in vitro and in vivo.The human gastric cancer cell lines AGS and MGC803 were selected as in vitro models. Wound-healing migration assay and Transwell invasion assay were carried out to determine the effects of As4S4 on cell migration and invasion. The expressions of E-cadherin, ?-catenin, Sp1, KLF4, and VEGF were measured by Western blotting analysis. The activities of matrix metalloproteinase (MMP)-2 and MMP-9 in MGC803 cells were demonstrated by zymography assay. A mouse xenograft model was established by inoculation with MGC803 cells, then intraperitoneal injected with As4S4 for 3 weeks and monitored for body weight and tumor changes. Finally, the inhibition rate of tumor growth was calculated, and the expression of proteins and genes associated with tumor invasion and metastasis in tumor tissues were measured by immunohistochemistry, Western blotting, and real-time polymerase chain reaction assay.As4S4 significantly inhibited the migration and invasion of gastric cancer cell lines. The expression of E-cadherin and KLF4 was upregulated, while the expressions of ?-catenin, VEGF, and Sp1 were downregulated following treatment with As4S4. Moreover, the protease activities of MMP-2 and MMP-9 were suppressed by As4S4 in MGC803 cells. Meanwhile, As4S4 effectively suppressed the abilities of tumor growth and invasion in the xenograft tumor model. We found that As4S4 upregulated the expression of E-cadherin and downregulated the expression of ?-catenin, Sp1, VEGF, and CD34 in mouse tumor tissues, consistent with the results in vitro.As4S4 inhibited the migration and invasion of gastric cancer cells by blocking tumor cell adhesion, decreasing the ability of tumor cells to destroy the basement membrane, and therefore suppressing their angiogenesis.

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NFATc3 mediates the sensitivity of gastric cancer cells to arsenic sulfide.

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NFATc3 mediates the sensitivity of gastric cancer cells to arsenic sulfide.

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