Roles of NAD+ and Its Metabolites Regulated Calcium Channels in Cancer

Peilin Yu,Mingxiang Wang,Yan Liang,Xiaobo Cai,Wei Yang

doi:10.3390/molecules25204826

Abstract

Nicotinamide adenine dinucleotide (NAD+) is an essential cofactor for redox enzymes, but also moonlights as a regulator for ion channels, the same as its metabolites. Ca2+ homeostasis is dysregulated in cancer cells and affects processes such as tumorigenesis, angiogenesis, autophagy, progression, and metastasis. Herein, we summarize the regulation of the most common calcium channels (TRPM2, TPCs, RyRs, and TRPML1) by NAD+ and its metabolites, with a particular focus on their roles in cancers. Although the mechanisms of NAD+ metabolites in these pathological processes are yet to be clearly elucidated, these ion channels are emerging as potential candidates of alternative targets for anticancer therapy.

Highlights

Nicotinamide adenine dinucleotide (NAD+ ) is an essential biomolecule involved in many critical processes, especially in energy metabolism and electron transfer
NAD+ can be generated from nicotinamide mononucleotide (NMN) via nicotinamide mononucleotide adenyltransferases 1–3 (NMNATs), and NMN is synthesized in a salvage pathway via NAM riboside (NR) by nicotinamide riboside kinases 1 and 2 (NRK1/2) or NAM by nicotinamide phosphoribosyltransferase (NAMPT)
Considering the important role of Ca2+ homeostasis in malignant transformation, tumor progression, and response to treatment [22], we review in this article the evidence implicating NAD+ and its metabolites as regulators of calcium channels, and the function of these ion channels in cancer, aiming to shed light on the mechanisms of NAD+ metabolites related to calcium signaling in tumorigenesis, metastasis, and therapy

Summary

Introduction

Nicotinamide adenine dinucleotide (NAD+ ) is an essential biomolecule involved in many critical processes, especially in energy metabolism and electron transfer. It has been reported that changes in NAD+ concentration and/or the NAD+ :NADH ratio can induce DNA repair and increase cell defense, by regulating diverse signaling pathways and transcriptional events, and plays an important role in cancer progression [13,14]. Besides the NAD+ /NADH system, another distinctive biochemical characteristic in carcinogenesis is the increased availability of the anabolic coenzyme NADPH Cancer cells adapt their metabolism to fulfill their increased demand for energy, biosynthetic intermediates, and to counter aerobic respiration-induced oxidative stress by diverting glycolysis to pentose phosphate pathway (PPP). During this process, NADPH is produced to counteract reactive oxygen species (ROS) and to act as a cofactor for the synthesis of nucleotides, proteins, and fatty acids [19].

Effects

Schematic

Findings

Conclusion