Gardella Kacie A, Muro Israel, Fang Gloria, Sarkar Krishnakali, Mendez Omayra, Wright Casey W
Institute for Cellular and Molecular Biology, The University of Texas at Austin, Austin, TX, USA.
Division of Pharmacology and Toxicology, and The Center for Molecular and Cellular Toxicology, College of Pharmacy, The University of Texas at Austin, Austin, TX, USA.
Oncotarget. 2016 Mar 8;7(10):10710-22. doi: 10.18632/oncotarget.7539.
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.
芳烃受体核转运蛋白（ARNT）参与外源性物质和低氧反应，我们之前的研究表明，ARNT还通过改变RelB亚基的DNA结合活性来调节核因子-κB（NF-κB）信号通路。然而，我们最初关于ARNT介导的RelB调节的研究是基于同时抑制两种ARNT异构体，即异构体1和3，因此无法对它们各自的功能进行研究。我们在此发现，虽然正常淋巴细胞中异构体1和3的水平相当，但淋巴系统恶性肿瘤中ARNT异构体1的水平会升高。ARNT异构体1的这些升高水平对这些癌细胞的增殖至关重要，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）细胞系中抑制异构体1会引发S期细胞周期停滞、自发凋亡，并使细胞对阿霉素治疗敏感。此外，同时抑制RelB或p53与ARNT异构体1可防止细胞周期停滞并阻断阿霉素诱导的凋亡。我们的研究结果共同表明，某些血液癌症依赖ARNT异构体1通过拮抗RelB和p53依赖性细胞周期停滞及凋亡来促进增殖。重要的是，我们的结果确定ARNT异构体1是抗癌治疗的潜在靶点。
