Dietary nitrate supplementation prevents radiotherapy-induced xerostomia

Xiaoyu Feng,Lei Hu,Chunmei Zhang,Liang Hu,Shimin Chang,Jingsong Wang,Bin Zhao,Dengsheng Xia,Zhipeng Fan,Luyuan Jin,Baoxing Pang,Junji Xu,Songlin Wang,Xingmin Qu,Zhifang Wu,Yipu Xu

doi:10.7554/elife.70710

Abstract

Management of salivary gland hypofunction caused by irradiation (IR) therapy for head and neck cancer remains lack of effective treatments. Salivary glands, especially the parotid gland, actively uptake dietary nitrate and secrete it into saliva. Here, we investigated the effect of dietary nitrate on the prevention and treatment of IR-induced parotid gland hypofunction in miniature pigs, and elucidated the underlying mechanism in human parotid gland cells. We found that nitrate administration prevented IR-induced parotid gland damage in a dose-dependent manner, by maintaining the function of irradiated parotid gland tissue. Nitrate could increase sialin expression, a nitrate transporter expressed in the parotid gland, making the nitrate-sialin feedback loop that facilitates nitrate influx into cells for maintaining cell proliferation and inhibiting apoptosis. Furthermore, nitrate enhanced cell proliferation via the epidermal growth factor receptor (EGFR)-protein kinase B (AKT)-mitogen-activated protein kinase (MAPK) signaling pathway in irradiated parotid gland tissue. Collectively, nitrate effectively prevented IR-induced xerostomia via the EGFR-AKT-MAPK signaling pathway. Dietary nitrate supplementation may provide a novel, safe, and effective way to resolve IR-induced xerostomia.

Highlights

Head and neck cancer (HNC) is the sixth most common malignancy worldwide (Torre et al, 2015).Irradiation (IR) is an important treatment approach for HNC
We found that nitrate administration increased phosphorylation of epidermal growth factor receptor (EGFR), AKT, and extracellular regulated protein kinase (ERK) (Figure 6a, Figure 6 source data1)
In the nitrate group in vivo compared with the IR control and sham groups that were consistent with our in vitro study (Figure 6e, Figure 6 source data5). These results suggested that a nitrate-sialin feedback loop could mediate cell proliferation to protect the parotid gland from IR damage via the EGFR–AKT–mitogen-activated protein kinase (MAPK) signaling pathway (Figure 6f)

Summary

INTRODUCTION

Head and neck cancer (HNC) is the sixth most common malignancy worldwide (Torre et al, 2015). Many studies have attempted to treat salivary hypofunction using gene transfer, stem cell transplantation, or salivary gland regeneration These studies have elucidated the mechanisms involved in xerostomia, and allowed for development of new treatments for xerostomia (Vissink et al, 2010; Vissink, van Luijk, Langendijk, & Coppes, 2015). Sialin transports nitrate and other essential cellular substances such as glutamate and aspartate, and contributes to maintenance of acinar cells physiological function (Qin et al, 2012) It is unclear why sialin is most strongly expressed in the parotid gland and facilitates nitrate influx into the gland. We investigated the preventive and therapeutic effects of dietary nitrate supplementation on IR-induced salivary gland hypofunction using an established miniature pig model, and characterized the mechanism underlying these effects

RESULTS

DISCUSSION

MATERIALS AND METHODS