Radioresistant Nasopharyngeal Carcinoma Cells Exhibited Decreased Cisplatin Sensitivity by Inducing SLC1A6 Expression.

Wenwen Hao,Xiaoping Lin,Linhui Cao,Lisha Wu,Yanfeng Chen,Jingshu Wang,Li Ning,Jinxiu Yu

doi:10.3389/fphar.2021.629264

Abstract

Cisplatin-based regimens are commonly used for the treatment of nasopharyngeal carcinoma (NPC) in patients who receive concurrent chemoradiotherapy. The sensitivity of NPC cells to cisplatin is closely associated with the efficacy of radiation therapy. In this study, we established two radioresistant NPC cell lines, HONE1-IR and CNE2-IR, and found that both cell lines showed reduced sensitivity to cisplatin. RNA-sequence analysis showed that SLC1A6 was upregulated in both HONE1-IR and CNE2-IR cell lines. Downregulation of SLC1A6 enhanced cisplatin sensitivity in these two radioresistant NPC cell lines. It was also found that the expression of SLC1A6 was induced during radiation treatment and correlated with poor prognosis of NPC patients. Notably, we observed that upregulation of SLC1A6 led to elevating level of glutamate and the expression of drug-resistant genes, resulted in reduced cisplatin sensitivity. Our findings provide a rationale for developing a novel therapeutic target for NPC patients with cisplatin resistance.

Highlights

Nasopharyngeal carcinoma (NPC) is a malignant tumor in the head and neck with high incidence in southern China and Southeast Asia (Chen et al, 2019; Ji et al, 2019)
We found that the radioresistant nasopharyngeal carcinoma (NPC) cells acquired the characteristic of reduced cisplatin sensitivity, which was associated with the upregulation of SLC1A6
As the sensitivity to cisplatin is closely associated with radiotherapy efficacy, we compared the sensitivity to cisplatin in radioresistant NPC and their parental cells

Summary

Introduction

Nasopharyngeal carcinoma (NPC) is a malignant tumor in the head and neck with high incidence in southern China and Southeast Asia (Chen et al, 2019; Ji et al, 2019). According to the guidelines of the National Comprehensive Cancer Network (NCCN), radiotherapy and cisplatin-based regimens are the main treatments for NPC patients (Pfister et al, 2020). The cisplatin-based concurrent chemoradiotherapy has been proven to improve the outcome of early and locally advanced NPC (Chen et al, 2011). There are a small portion of patients who did not response effectively or became recurrent to these treatments, and their prognosis remains poor (Chen et al, 2011; Karam et al, 2016). Some studies have revealed that cancer cells could acquire cisplatin resistance after radiation therapy (Eichholtz-Wirth, 1995; Zhuang et al, 2019). Based on our clinical observations, the phenomenon of cisplatin resistance is commonly seen in NPC patients who resistant to radiotherapy. The association of cisplatin and radiation resistance is elusive

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Conclusion