1α,25(OH)2D3 Radiosensitizes Cancer Cells by Activating the NADPH/ROS Pathway
1α,25(OH)2D3 Radiosensitizes Cancer Cells by Activating the NADPH/ROS Pathway
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1α,25(OH)2D3 通过激活 NADPH/ROS 途径使癌细胞放射增敏
DOI：
10.3389/fphar.2020.00945
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发表时间：
2020-08-07
影响因子：
5.6
通讯作者：
Li, Bing-Yan
中科院分区：
文献类型：
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作者：
Ji, Min-Tao;Nie, Jing;Li, Bing-Yan
肿瘤的放射耐药影响放射治疗的效果。越来越多的数据表明，1 α,25(OH)(2)D(3)在多种癌症中是一种潜在的抗癌分子。在本研究中，我们研究了1 α，25(OH)(2)D(3)在体外和体内的辐射敏感效应及其潜在机制。我们发现1 α，25(OH)(2)D(3)通过促进NADPH氧化酶- ros -凋亡轴增强肺癌和卵巢癌细胞的放射敏感性。与仅接受放射治疗的组相比，1 α,25(OH)(2)D(3)和放射联合治疗的癌细胞的生存率和自我更新能力降低。与单纯放疗组相比，联合放疗组细胞凋亡和ROS均明显增加。此外，细胞内ROS清除剂n -乙酰- l-半胱氨酸逆转了1 α，25(OH)(2)D-3诱导的细胞凋亡和ROS，表明1 α，25(OH)(2)D(3)通过促进ROS诱导的细胞凋亡，增强了癌细胞在体外的放射敏感性。此外，我们的研究结果表明，1 α,25(OH)(2)D(3)通过激活NADPH氧化酶复合物NOX4， p22（phox）和p47（phox）来促进ROS水平。此外，维生素D受体（VDR）的敲除消除了1 α，25(OH)(2)D-3的放射致敏作用，这证实了1 α，25(OH)(2)D(3)对依赖VDR的肿瘤细胞具有放射致敏作用。同样，我们的研究也证明了维生素D(3)在体内增强了癌细胞的放射敏感性，延长了肿瘤小鼠的总体生存期。综上所述，这些结果表明，1 α,25(OH)(2)D(3)增强了依赖于VDR的放射敏感性，并激活了NADPH氧化酶- ros -凋亡轴。我们的研究结果表明，1 α,25(OH)(2)D(3)联合放疗可增强肺和卵巢细胞的放射敏感性，可能提供一种新的联合治疗策略。
The radioresistance of tumors affect the outcome of radiotherapy. Accumulating data suggest that 1 alpha,25(OH)(2)D(3)is a potential anti-oncogenic molecule in various cancers. In the present study, we investigated the radiosensitive effects and underlying mechanisms of 1 alpha,25(OH)(2)D(3)in vitroandin vivo. We found that 1 alpha,25(OH)(2)D(3)enhanced the radiosensitivity of lung cancer and ovarian cancer cells by promoting the NADPH oxidase-ROS-apoptosis axis. Compared to the group that only received radiation, the survival fraction and self-renewal capacity of cancer cells treated with a combination of 1 alpha,25(OH)(2)D(3)and radiation were decreased. Both apoptosis and ROS were significantly increased in the combination group compared with the radiation only group. Moreover, N-acetyl-L-cysteine, a scavenger of intracellular ROS, reversed the apoptosis and ROS induced by 1 alpha,25(OH)(2)D-3, indicating that 1 alpha,25(OH)(2)D(3)enhanced the radiosensitivity of cancer cellsin vitroby promoting ROS-induced apoptosis. Moreover, our results demonstrated that 1 alpha,25(OH)(2)D(3)promoted the ROS levelviaactivating NADPH oxidase complexes, NOX4, p22(phox), and p47(phox). In addition, knockdown of the vitamin D receptor (VDR) abolished the radiosensitization of 1 alpha,25(OH)(2)D-3, which confirmed that 1 alpha,25(OH)(2)D(3)radiosensitized tumor cells that depend on VDR. Similarly, our study also evidenced that vitamin D(3)enhanced the radiosensitivity of cancer cellsin vivoand extended the overall survival of mice with tumors. In summary, these results demonstrate that 1 alpha,25(OH)(2)D(3)enhances the radiosensitivity depending on VDR and activates the NADPH oxidase-ROS-apoptosis axis. Our findings suggest that 1 alpha,25(OH)(2)D(3)in combination with radiation enhances lung and ovarian cell radiosensitivity, potentially providing a novel combination therapeutic strategy.