Aryl hydrocarbon receptor nuclear translocator (ARNT) isoforms control lymphoid cancer cell proliferation through differentially regulating tumor suppressor p53 activity.
Aryl hydrocarbon receptor nuclear translocator (ARNT) isoforms control lymphoid cancer cell proliferation through differentially regulating tumor suppressor p53 activity.
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DOI：
10.18632/oncotarget.7539
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发表时间：
2016-03-08
期刊：
影响因子：
--
通讯作者：
Wright CW
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文献类型：
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作者：
Gardella KA;Muro I;Fang G;Sarkar K;Mendez O;Wright CW
芳香烃受体核转位蛋白（ARNT）参与外源性和缺氧反应，我们以前发现ARNT也通过改变RelB亚基的DNA结合活性调节核因子-κB（NF-κB）信号传导。然而，我们对ARNT介导的RelB调节的初步研究是基于同时抑制两种ARNT亚型（亚型1和3），并排除了对它们各自功能的检查。我们发现，正常淋巴细胞具有相同水平的同种型1和3，淋巴恶性肿瘤表现出转移到更高水平的ARNT同种型1。ARNT同种型1的这些升高的水平对于这些癌细胞的增殖是关键的，因为在人多发性骨髓瘤（MM）细胞系和间变性大细胞淋巴瘤（ALCL）细胞系中同种型1的抑制，触发S期细胞周期停滞、自发凋亡和对阿霉素治疗敏感的细胞。此外，RelB或p53与ARNT亚型1的共抑制阻止了细胞周期停滞并阻断了阿霉素诱导的细胞凋亡。总之，我们的研究结果表明，某些血液癌症依赖于ARNT亚型1通过拮抗RelB和p53依赖性细胞周期阻滞和凋亡来增强增殖。值得注意的是，我们的研究结果确定ARNT亚型1作为抗癌治疗的潜在靶点。
The aryl hydrocarbon receptor nuclear translocator (ARNT) is involved in xenobiotic and hypoxic responses, and we previously showed that ARNT also regulates nuclear factor-κB (NF-κB) signaling by altering the DNA binding activity of the RelB subunit. However, our initial study of ARNT-mediated RelB modulation was based on simultaneous suppression of the two ARNT isoforms, isoform 1 and 3, and precluded the examination of their individual functions. We find here that while normal lymphocytes harbor equal levels of isoform 1 and 3, lymphoid malignancies exhibit a shift to higher levels of ARNT isoform 1. These elevated levels of ARNT isoform 1 are critical to the proliferation of these cancerous cells, as suppression of isoform 1 in a human multiple myeloma (MM) cell line, and an anaplastic large cell lymphoma (ALCL) cell line, triggered S-phase cell cycle arrest, spontaneous apoptosis, and sensitized cells to doxorubicin treatment. Furthermore, co-suppression of RelB or p53 with ARNT isoform 1 prevented cell cycle arrest and blocked doxorubicin induced apoptosis. Together our findings reveal that certain blood cancers rely on ARNT isoform 1 to potentiate proliferation by antagonizing RelB and p53-dependent cell cycle arrest and apoptosis. Significantly, our results identify ARNT isoform 1 as a potential target for anticancer therapies.