Pathogenesis of aryl hydrocarbon receptor-mediated development of lymphoma is associated with increased cyclooxygenase-2 expression
Pathogenesis of aryl hydrocarbon receptor-mediated development of lymphoma is associated with increased cyclooxygenase-2 expression
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DOI：
10.2353/ajpath.2007.070406
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发表时间：
2007-11-01
影响因子：
6
通讯作者：
Matsumura, Furnio
中科院分区：
文献类型：
--
作者：
Vogel, Christoph F. A.;Li, Wen;Matsumura, Furnio
流行病学研究表明，接触农药和二恶英等环境污染物会导致淋巴瘤和白血病的发病。在这里，我们发现芳香烃受体(AhR)被2，3，7，8-四氯二苯并对二恶英(TCDD)激活，导致三种不同的淋巴瘤细胞系失去细胞程序性死亡(凋亡)反应，这在癌症的发展中起着关键作用，特别是淋巴瘤和白血病。AhR在体外对细胞凋亡的抑制作用与环氧合酶-2(COX-2)的表达明显增加以及参与细胞凋亡的B细胞淋巴瘤-2(BCL-2)家族基因(包括Bclxl和Mcl-1)在几种淋巴瘤细胞中的表达下调有关。环氧合酶-2抑制剂NS-398和AhR拮抗剂3‘-中氧基-4’-硝基-4‘-硝酮可在体外阻断TCDD诱导的细胞凋亡抵抗。此外，使用微正电子发射断层成像，在体内的发现表明，暴露于TCDD促进了淋巴瘤的发展。C57BL/10J小鼠浅表淋巴结中COX-2表达明显增加。结果表明，AhR激活和COX-2过表达可能代表了淋巴瘤细胞株的抗凋亡机制，可能与体内淋巴瘤的发生发展有关。
Epidemiological studies indicate that exposure to environmental pollutants such as pesticides and dioxins leads to the pathogenesis of lymphoma and leukemia. Here, we show that activation of the aryl hydrocarbon receptor (AhR) by 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) resulted in loss of the programmed cell death (apoptosis) response in three different lymphoma cell lines, which plays a key role in the development of cancer, especially lymphoma and leukemia. The AhR- mediated inhibition of apoptosis in vitro was associated with a clear increase of cyclooxygenase-2 (COX-2) and deregulation of genes of the B-cell lymphoma-2 (Bcl-2) family involved in apoptosis including Bcl-xl and Mcl-1 in several lymphoma cell fines. Treatment with the COX-2 inhibitor NS-398 and the AhR antagonist 3'-medioxy-4'-nitroflavone abolished the TCDD-induced resistance of apoptosis in vitro. Furthermore, using micropositron emission tomography imaging, in vivo findings demonstrated that exposure to TCDD promotes the development of lymphoma. in superficial lymph nodes of C57BL/10J mice, which was associated with a marked increase of COX-2 expression in the affected lymph nodes. The results indicate that AhR activation and COX-2 overexpression likely represent a mechanism of resistance to apoptosis in lymphoma cell lines that might be relevant for the development of lymphoma in vivo.