Aryl hydrocarbon receptor counteracts pharmacological efficacy of doxorubicin via enhanced AKR1C3 expression in triple negative breast cancer cells
Aryl hydrocarbon receptor counteracts pharmacological efficacy of doxorubicin via enhanced AKR1C3 expression in triple negative breast cancer cells
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芳基烃受体通过增强三阴性乳腺癌细胞中 AKR1C3 的表达来抵消阿霉素的药理功效
DOI：
10.1016/j.bbrc.2019.06.119
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发表时间：
2019
影响因子：
3.1
通讯作者：
Nemoto Kiyomitsu
中科院分区：
文献类型：
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作者：
Yamashita Naoya;Kanno Yuichiro;Saito Nao;Terai Kensuke;Sanada Noriko;Kizu Ryoichi;Hiruta Nobuyuki;Park Youngjin;Bujo Hideaki;Nemoto Kiyomitsu
三阴性乳腺癌（TNBC）预后差，因为没有有效的靶向治疗。在本研究中，我们证明了芳香烃受体（AhR）在介导化疗剂阿霉素（DOX）对TNBC化疗敏感性的影响中的关键作用。首先，我们建立AhR敲除（KO）MDA-MB 231 TNBC细胞。DOX的细胞毒性作用在AhR KO细胞中比在亲本细胞中更明显。此外，我们的结果表明，相对于亲代细胞，AhR KO细胞显示DOX代谢酶醛酮还原酶（AKR）1C 3的表达下调。此外，发现AhR增强AKR 1C 3启动子报告活性，表明AKR 1C 3 mRNA转录被AhR激活。此外，我们的研究结果证实，AKR 1C 3表达的下调增强了MDA-MB 231细胞对DOX的敏感性。最后，AhR和AKR 1C 3在人乳腺癌中的表达呈正相关。综上所述，我们的结果表明，AhR通过调节TNBC细胞中AKR 1C 3的表达而参与DOX敏感性。
Triple-negative breast cancer (TNBC) is associated with poor prognosis, because of no effective targeted therapy. In the present study, we demonstrated the crucial role of the aryl hydrocarbon receptor (AhR) in mediating the effects of the chemotherapeutic agent doxorubicin (DOX) in the chemotherapeutic sensitivity of TNBC. Firstly, we established AhR knockout (KO) MDA-MB 231 TNBC cells. The cytotoxic effects of DOX were more pronounced in AhR KO cells than in parental cells. In addition, our results indicated that AhR KO cells showed downregulated expression of DOX-metabolism enzyme, aldo-keto reductase (AKR) 1C3, relative to those of parental cells. Furthermore, AhR was found to enhance AKR1C3 promoter reporter activity, suggesting that AKR1C3 mRNA transcription is activated by AhR. Additionally, our findings confirmed that the downregulation of AKR1C3 expression enhanced DOX sensitivity in MDA-MB 231 cells. Finally, AhR and AKR1C3 expression were positively correlated in human breast cancer. Taken together, our results suggested that AhR is involved in DOX sensitivity by regulating AKR1C3 expression in TNBC cells.