Beijing Institute of Dental Research, Beijing Stomatological Hospital & School of Stomatology, Capital Medical University, No. 4 Tiantanxili, Dongcheng District, Beijing, China.
Cancer Lett. 2012 May 1;318(1):93-8. doi: 10.1016/j.canlet.2011.12.005. Epub 2011 Dec 9.
Nuclear factor erythroid derived 2 like 2 (Nrf2) is a critical transcriptional factor in mediating cellular defense mechanisms against oxidative stress or electrophiles. Arsenic has been reported to induce malignant transformation of human cells through Nrf2-dependent signaling pathway. However, arsenic is also a promising cancer therapeutic drug for solid tumors, including oral squamous cell carcinoma (OSCC). It is still unclear how Nrf2 may mediate cellular response of OSCC cells when treated with arsenic. In order to fully understand the impact of arsenic on Nrf2 signaling in human OSCC, we examined expression of Nrf2 and Nrf2-regulated genes in arsenic trioxide (ATO)-treated OSCC cells in vitro and in ATO-treated OSCC xenografts. ATO had anti-cancer effects on both cultured OSCC cells and OSCC xenografts by inhibiting cell growth, suppressing angiogenesis and inducing apoptosis. ATO activated a silent Nrf2 pathway in cultured OSCC cells as shown by induction of Nrf2 and Nrf2-regulated genes, NAD(P)H:quinone oxidoreductase 1 (NQO1) and heme oxygenase-1 (HO-1), in a dose-dependent manner. On the contrary, Nrf2 pathway became active in OSCC xenograft tumors, and ATO treatment down-regulated expression of Nrf2 and Nrf2-regulated genes. Our study clearly demonstrated opposite effects of ATO on Nrf2 pathway in OSCC cells in vitro and in vivo.
核因子红细胞衍生 2 样 2（Nrf2）是一种重要的转录因子，可介导细胞对氧化应激或亲电物质的防御机制。已有报道称，砷通过 Nrf2 依赖性信号通路诱导人类细胞恶性转化。然而，砷也是一种有前途的治疗实体瘤的癌症药物，包括口腔鳞状细胞癌（OSCC）。目前尚不清楚 Nrf2 在砷处理 OSCC 细胞时如何介导细胞反应。为了充分了解砷对人 OSCC 中 Nrf2 信号的影响，我们研究了三氧化二砷（ATO）处理体外 OSCC 细胞和 ATO 处理 OSCC 异种移植瘤中 Nrf2 和 Nrf2 调节基因的表达。ATO 通过抑制细胞生长、抑制血管生成和诱导细胞凋亡，对培养的 OSCC 细胞和 OSCC 异种移植瘤均具有抗癌作用。ATO 以剂量依赖性方式诱导 Nrf2 和 Nrf2 调节基因 NAD（P）H：醌氧化还原酶 1（NQO1）和血红素加氧酶-1（HO-1）的表达，从而激活培养的 OSCC 细胞中沉默的 Nrf2 通路。相反，Nrf2 通路在 OSCC 异种移植瘤中变得活跃，ATO 处理下调了 Nrf2 和 Nrf2 调节基因的表达。我们的研究清楚地表明，ATO 在体外和体内对 OSCC 细胞中的 Nrf2 通路具有相反的作用。
