Beta-naphthoflavone (DB06732) mediates estrogen receptor-positive breast cancer cell cycle arrest through AhR-dependent regulation of PI3K/AKT and MAPK/ERK signaling.
Beta-naphthoflavone (DB06732) mediates estrogen receptor-positive breast cancer cell cycle arrest through AhR-dependent regulation of PI3K/AKT and MAPK/ERK signaling.
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DOI：
10.1093/carcin/bgt356
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发表时间：
2014-03
期刊：
影响因子：
4.7
通讯作者：
Chun Wang;Canxin Xu;Yiwen Bu;K. Bottum;S. Tischkau
中科院分区：
文献类型：
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作者：
Chun Wang;Canxin Xu;Yiwen Bu;K. Bottum;S. Tischkau
β-萘黄酮（BNF，DB06732）是芳香烃受体（AhR）的激动剂，是一种假定的化疗药物，在体内对乳腺癌具有抗肿瘤活性。然而，BNF发挥这种抗肿瘤作用的机制仍不清楚。因此，我们探究了BNF在人乳腺癌细胞中的抗肿瘤作用机制。本研究表明，BNF抑制细胞增殖，并诱导细胞周期停滞在G0/G1期，同时下调细胞周期蛋白D1/D3和细胞周期蛋白依赖性激酶4（CDK4），上调p21（Cip1/Waf1），从而在雌激素受体（ER）阳性的MCF - 7细胞中导致类似衰老的表型，但在ER阴性的MDA - MB - 231细胞中则没有。此外，BNF抑制PI3K/AKT信号通路，PI3K抑制剂LY294,002对细胞周期蛋白D1/D3、CDK4和细胞周期表现出与BNF相同的抑制作用。有趣的是，BNF激活丝裂原活化蛋白激酶 - 细胞外信号调节激酶（MAPK - ERK）信号通路，更值得注意的是，MEK抑制剂PD98059显著阻断BNF诱导的细胞周期停滞以及p21（Cip1/Waf1）的上调。此外，特异性ERα和AhR小干扰RNA研究表明，在BNF诱导的p21（Cip1/Waf1）表达中需要ERα，并且BNF介导的细胞周期停滞以及对AKT和ERK信号通路的调节是依赖于AhR的。综上所述，依赖于AhR对PI3K/AKT通路的抑制、MAPK/ERK的激活以及对ERα的调节是BNF介导的乳腺癌抗肿瘤作用的一种新机制，这可能代表一种在未来临床试验中可利用的有前景的策略。
Beta-naphthoflavone (BNF, DB06732) is an agonist of aryl hydrocarbon receptor (AhR) and a putative chemotherapeutic agent that has antitumor activity against mammary carcinomas in vivo. However, the mechanism by which BNF exerts this antitumor effect remains unclear. Thus, we explored mechanisms of BNF's antitumor effects in human breast cancer cells. This study showed that BNF suppressed cell proliferation and induced cell cycle arrest in the G0/G1 phase with downregulation of cyclin D1/D3 and CDK4 and upregulation of p21(Cip1/Waf1), leading to a senescence-like phenotype in estrogen receptor (ER)-positive MCF-7 cells, but not in ER-negative MDA-MB-231 cells. In addition, BNF inhibited PI3K/AKT signaling, and the PI3K inhibitor, LY294,002, exhibited the same inhibitory effects on cyclinD1/D3, CDK4 and the cell cycle as BNF. Interestingly, BNF activated mitogen-activated protein kinase-extracellular signal-regulated kinase (MAPK-ERK) signaling, and more notably, MEK inhibitor PD98059 significantly blocked the BNF-induced cell cycle arrest and upregulation of p21(Cip1/Waf1). Furthermore, specific ERα and AhR siRNA studies indicate that ERα is required in BNF-induced p21(Cip1/Waf1) expression, and BNF-mediated cell cycle arrest and modulation of AKT and ERK signaling is AhR-dependent. Taken together, AhR-dependent inhibition of the PI3K/AKT pathway, activation of MAPK/ERK and modulation of ERα is a novel mechanism underlying BNF-mediated antitumor effects in breast cancer, which may represent a promising strategy to be exploited in future clinical trials.