Bu Hengtao, Tang Sensheng, Liu Guiting, Miao Chenkui, Zhou Xiang, Yang Haiwei, Liu Bianjiang
Department of Urology, the First Affiliated Hospital of Nanjing Medical University, Nanjing 210029, China.
Department of Urology, the First Affiliated Hospital of Nanjing Medical University, Nanjing 210029, China.
Toxicology. 2023 Apr;488:153465. doi: 10.1016/j.tox.2023.153465. Epub 2023 Feb 23.
Dibutyl phthalate (DBP) is widely used in perfumes, cosmetics, shampoos and medical devices. It is ubiquitous in the environment and greatly endangers people's health. Several studies have reported that being exposed to it can promote the development of lung cancer, breast cancer, hepatoma, and multiple myeloma. However, there are still few studies on the specific molecular mechanism and prevention methods of DBP promoting the progression of prostate cancer. This study, in silico, in vitro and in vivo, aims to explore the promoting effect of DBP on prostate cancer cell proliferation. In silico analysis, we obtained a set of DBP interactive genes by utilizing TCGA, CTD and GEO database. These genes are mainly enriched in cell cycle regulatory pathways and they have high degree of homogeneity. We found that these genes shared one transcription factor - Forkhead Box M1 (FOXM1) by performing Chip-X Enrichment Analysis (Version 3.0). FOXM1, once called the 2010 Molecule of the Year, aberrantly expressed in up to 20 kinds of tumors. In vitro experiments, we used DBP at concentrations of 10 M and 5 * 10 M to treat C4-2 and PC3 cells for 6 days, respectively. Cell viability was promoted significantly. When Natura-α was added in the background of above-mentioned concentration of DBP, this effect was significantly inhibited. In addition, we also found that DBP can interfering with the efficacy of enzalutamide therapy. The introduction of Natura-α can also reverse this phenomenon. In vivo, subcutaneous tumor formation experiments in nude mice, 800 mg/kg/day DBP can promote the growth of prostate cancer. This phenomenon was suppressed when Natura-α (100 mg/kg/day) was added. Based on the results of the above three levels, we confirmed that DBP can target FOXM1 to promote prostate cancer cell proliferation. Natura-α can reverse its cancer-promoting effect. This study provides new insights into the impact of DBP on prostate cancer.
邻苯二甲酸二丁酯（DBP）广泛应用于香水、化妆品、洗发水和医疗设备中。它在环境中无处不在，对人体健康危害极大。多项研究报告称，接触DBP会促进肺癌、乳腺癌、肝癌和多发性骨髓瘤的发展。然而，关于DBP促进前列腺癌进展的具体分子机制和预防方法的研究仍然很少。本研究通过计算机模拟、体外和体内实验，旨在探讨DBP对前列腺癌细胞增殖的促进作用。在计算机模拟分析中，我们利用TCGA、CTD和GEO数据库获得了一组DBP相互作用基因。这些基因主要富集在细胞周期调控通路中，并且具有高度的同质性。通过进行芯片-X富集分析（3.0版），我们发现这些基因共享一个转录因子——叉头框M1（FOXM1）。FOXM1曾被称为2010年度分子，在多达20种肿瘤中异常表达。在体外实验中，我们分别用10 μM和5×10 μM浓度的DBP处理C4-2和PC3细胞6天。细胞活力得到显著促进。当在上述DBP浓度背景下添加Natura-α时，这种作用被显著抑制。此外，我们还发现DBP会干扰恩杂鲁胺治疗的疗效。引入Natura-α也可以逆转这种现象。在体内，对裸鼠进行皮下肿瘤形成实验，800 mg/kg/天的DBP可促进前列腺癌生长。当添加Natura-α（100 mg/kg/天）时，这种现象受到抑制。基于上述三个层面的结果，我们证实DBP可靶向FOXM1促进前列腺癌细胞增殖。Natura-α可逆转其促癌作用。本研究为DBP对前列腺癌的影响提供了新的见解。
