1α,25(OH)2D3 Radiosensitizes Cancer Cells by Activating the NADPH/ROS Pathway.

Min-Tao Ji,Wen-Tao Hu,Lei Chang,Xue-Fei Nie,Ai-Qing Wang,Zeng-Li Zhang,Jing Nie,Hai-Long Pei,Guang-Ming Zhou,Jian-Mei Wan,Bing-Yan Li

doi:10.3389/fphar.2020.00945

Abstract

The radioresistance of tumors affect the outcome of radiotherapy. Accumulating data suggest that 1α,25(OH)2D3 is a potential anti-oncogenic molecule in various cancers. In the present study, we investigated the radiosensitive effects and underlying mechanisms of 1α,25(OH)2D3 in vitro and in vivo. We found that 1α,25(OH)2D3 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 1α,25(OH)2D3 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 1α,25(OH)2D3, indicating that 1α,25(OH)2D3 enhanced the radiosensitivity of cancer cells in vitro by promoting ROS-induced apoptosis. Moreover, our results demonstrated that 1α,25(OH)2D3 promoted the ROS level via activating NADPH oxidase complexes, NOX4, p22phox, and p47phox. In addition, knockdown of the vitamin D receptor (VDR) abolished the radiosensitization of 1α,25(OH)2D3, which confirmed that 1α,25(OH)2D3 radiosensitized tumor cells that depend on VDR. Similarly, our study also evidenced that vitamin D3 enhanced the radiosensitivity of cancer cells in vivo and extended the overall survival of mice with tumors. In summary, these results demonstrate that 1α,25(OH)2D3 enhances the radiosensitivity depending on VDR and activates the NADPH oxidase-ROS-apoptosis axis. Our findings suggest that 1α,25(OH)2D3 in combination with radiation enhances lung and ovarian cell radiosensitivity, potentially providing a novel combination therapeutic strategy.

Highlights

Malignant cancer is a disease with one of the highest mortality rates in the world
We found that 1a,25(OH)2D3 enhances the radiosensitivity of lung cancer and ovarian cancer cells that depend on vitamin D receptor (VDR) by promoting the NADPH oxidase-reactive oxygen species (ROS)-apoptosis axis
It has been reported that vitamin D and vitamin D analogs radiosensitized breast cancer and lung cancer cells through altering the nature of the autophagy, converting it from a protective form to a cytotoxic form in vitro (Sundaram and Gewirtz, 1999; Demasters et al, 2006; Bristol et al, 2012)

Summary

INTRODUCTION

The general treatment for malignant cancer is based on radical surgery, radiotherapy, and chemotherapy (Miller et al, 2016). 1a,25(OH)2D3 Promotes Radiosensitivity by NADPH/ROS for malignant cancers (Barker et al, 2015). The current challenge is to find a novel strategy to increase the radiosensitivity of malignant cancers. Ovarian cancer is a malignancy tumor with high mortality (Miller et al, 2016), due to the existence of ovarian cancer stem cells (Brabletz et al, 2005; Aguilar-Gallardo et al, 2012; Flesken-Nikitin et al, 2013). The mitochondrial and NADPH oxidase-derived ROS, combined with the radiotherapy, may increase the radiosensitivity of cancer cells (Chen et al, 2019; Mortezaee et al, 2019). We found that 1a,25(OH)2D3 enhances the radiosensitivity of lung cancer and ovarian cancer cells that depend on VDR by promoting the NADPH oxidase-ROS-apoptosis axis

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ETHICS STATEMENT