Melatonin Antagonizes Nickel-Induced Aerobic Glycolysis by Blocking ROS-Mediated HIF-1α/miR210/ISCU Axis Activation.

Mindi He,Yu Xi,Zhengping Yu,Zhou Zhou,Lei Zhang,Chao Zhou,Ling Mao,Xue Wang,Xiang Mei,Yonghui Lu

doi:10.1155/2020/5406284

Abstract

Nickel and its compounds, which are well-documented carcinogens, induce the Warburg effect in normal cells by stabilizing hypoxia-inducible factor 1α (HIF-1α). Melatonin has shown diverse anticancer properties for its reactive oxygen species- (ROS-) scavenging ability. Our aim was to explore how melatonin antagonized a nickel-induced increment in aerobic glycolysis. In the current work, a normal human bronchial epithelium cell line (BEAS-2B) was exposed to a series of nonlethal doses of NiCl2, with or without 1 mM melatonin. Melatonin attenuated nickel-enhanced aerobic glycolysis. The inhibition effects on aerobic glycolysis were attributed to the capability of melatonin to suppress the regulatory axis comprising HIF-1α, microRNA210 (miR210), and iron-sulfur cluster assembly scaffold protein (ISCU1/2). N-Acetylcysteine (NAC) manifested similar effects as melatonin in scavenging ROS, maintaining prolyl-hydroxylase activity, and mitigating HIF-1α transcriptional activity in nickel-exposed cells. Our results indicated that ROS generation contributed to nickel-caused HIF-1α stabilization and downstream signal activation. Melatonin could antagonize HIF-1α-controlled aerobic glycolysis through ROS scavenging.

Highlights

Nickel and its compounds are well-known carcinogens for nasal and lung carcinoma in occupationally exposed workers
We observed that a nonlethal dose of nickel increased glycolysis in BEAS-2B cells
The cell line and nickel dose are comparable to those applied in other nickel carcinogenesis researches [30, 31]

Summary

Introduction

Nickel and its compounds are well-known carcinogens for nasal and lung carcinoma in occupationally exposed workers. Nickel-associated pulmonary carcinomas have been confirmed by both epidemiologic and experimental evidence, the exact mechanism of nickel carcinogenesis remains unclear. Aerobic glycolysis is considered to play roles in nickel-induced cell transformation [2,3,4]. The metabolism pattern of tumor cells is characterized by aerobic glycolysis, the so-called Warburg effect [5]. On the other hand, enhanced glycolysis leads to the accumulation of lactic acid in the extracellular space. The process by which normal cells adopt glycolysis is presumed to play roles in the initiation phase of carcinogenesis [7]

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