Abstract
Glutaminase is a critical enzyme that catalyzes the process of glutaminolysis for energy synthesis. Meanwhile, glutaminase also contributes to the pathological process of various diseases, such as cancer, neurodegenerative diseases, and inflammation. This leads to the discovery of glutaminase inhibitors for therapeutical uses. However, the mechanisms of the beneficial therapeutical effect of glutaminase inhibitors are still unclear. This pilot study aimed to determine the impact of a well-characterized glutaminase inhibitor, compound 968 (C968), on Nrf2 signaling. We performed molecular docking, luciferase assay, and quantitative PCR to determine the activation of Nrf2 and the expression of several Nrf2-related genes. These experiments found that C968 induced the Nrf2 activation and promoted the expression of Nrf2, heme oxygenase-1 (HO-1), and NAD(P)H Quinone Dehydrogenase-1 (NQO-1). All findings provide evidence that Nrf2 activation could be one of the mechanisms contributing to the therapeutical activity of C968, but more studies are warranted to further confirm this mechanism.
Highlights
Glutaminase is a mitochondrial enzyme that converts glutamine to glutamate [1]
We evaluated the impact of compound 968 (C968) on Nrf2 activation using BV2 microglial cells stably expressing antioxidant element (ARE) luciferase reporters, which was generously provided by Dr Valeri Mossine from the University of Missouri
Most of the well-known Nrf2 activators are irreversible inhibitors of Keap1 with high electrophilic motifs that can covalently bind to the cysteine residue of Keap1 to enhance the disassociation of Nrf2 [23]
Summary
Glutaminase is a mitochondrial enzyme that converts glutamine to glutamate [1]. The expression and function of glutaminase is upregulated, which contributes to tumor growth in several types of cancer [2]. The glutaminase promotes the metabolism of glutamine and glutamate, which provides sufficient energy for tumor growth [3]. Glutamine metabolism contributes to the tumor metastasis process through interactions with the epithelial–mesenchymal transition (EMT), tumor immunology, and tumor microenvironment [4]. Glutaminase has been developed as an appealing target therapy for various cancers [5]. Numerous glutaminase inhibitors, such as compound 968 (C968, 5-(3-bromo-4(dimethylamino)phenyl)-2,2-dimethyl-2,3,5,6-tetrahydrobenzo[a] phenanthridin-4(1H)-one,
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