GADD45\u03b1 sensitizes cervical cancer cells to radiotherapy via increasing cytoplasmic APE1 level

Qing Li,Kui-Jun Chen,Jian-Min Wang,Jin-Lu Shan,Shu-Nan Wang,Kenneth D Westover,Cheng-Xiong Xu,Dong Wang,Hua Jin,Zhi-Wei Zhou,Xi Wei,Jia Luo

doi:10.1038/s41419-018-0452-x

Abstract

Radioresistance remains a major clinical challenge in cervical cancer therapy. However, the mechanism for the development of radioresistance in cervical cancer is unclear. Herein, we determined that growth arrest and DNA-damage-inducible protein 45α (GADD45α) is decreased in radioresistant cervical cancer compared to radiosensitive cancer both in vitro and in vivo. In addition, silencing GADD45α prevents cervical cancer cells from undergoing radiation-induced DNA damage, cell cycle arrest, and apoptosis. More importantly, our data show that the overexpression of GADD45α significantly enhances the radiosensitivity of radioresistant cervical cancer cells. These data show that GADD45α decreases the cytoplasmic distribution of APE1, thereby enhancing the radiosensitivity of cervical cancer cells. Furthermore, we show that GADD45α inhibits the production of nitric oxide (NO), a nuclear APE1 export stimulator, by suppressing both endothelial NO synthase (eNOS) and inducible NO synthase (iNOS) in cervical cancer cells. In conclusion, our findings suggest that decreased GADD45α expression significantly contributes to the development of radioresistance and that ectopic expression of GADD45α sensitizes cervical cancer cells to radiotherapy. GADD45α inhibits the NO-regulated cytoplasmic localization of APE1 through inhibiting eNOS and iNOS, thereby enhancing the radiosensitivity of cervical cancer cells.

Highlights

Cervical cancer is the fourth most common malignant disease[1] and one of the major causes of cancer-related death among females worldwide[2]
In agreement with the in vitro experimental results, clinical specimens presented with significantly reduced Growth arrest and DNAdamage-inducible protein 45α (GADD45α) expression compared to specimens from radiotherapy-sensitive patients (Fig. 2c), suggesting that decreased GADD45α expression correlates with radioresistance in cervical cancer
On the other hand, inhibiting nitric oxide (NO) production using a NOS inhibitor dramatically suppressed GADD45α-induced cytoplasmic apyrimidinic endonuclease 1 (APE1) accumulation (Fig. 7d). These findings indicate that GADD45α reduces cytoplasmic APE1 through the inhibition of NO production by reducing both inducible NO synthase (iNOS) and endothelial NO synthase (eNOS) expression in cervical cancer cells

Summary

Introduction

Cervical cancer is the fourth most common malignant disease[1] and one of the major causes of cancer-related death among females worldwide[2]. Radiotherapy is one of the most commonly used treatments for cervical cancer as it significantly reduces the risk of cervical cancer relapse[3]. Radiotherapy causes cell cycle arrest and tumor cell death by inducing DNA damage[5]. Aberrant DNA repair is one mechanism whereby cancer cells may become radioresistant. Growth arrest and DNAdamage-inducible protein 45α (GADD45α) is a radiationinducible gene[6] that is involved in DNA repair[7, 8]. Lu et al.[9] and Hur et al.[10] showed that the inactivation of GADD45α sensitized epithelial cancer cells and hepatoma cells, respectively, to radiation treatment, whereas Zhang et al.[11] and Official journal of the Cell Death Differentiation Association

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Conclusion