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Glioblastoma is an exceptionally difficult cancer to treat. Cancer is universally marked by epigenetic changes, which play key roles in sustaining a malignant phenotype, in addition to disease progression and patient survival. Studies have shown strong links between the cellular redox state and epigenetics. Nuclear factor (erythroid-derived 2)-like 2 (Nrf2) is a redox-sensitive transcription factor that upregulates endogenous antioxidant production, and is aberrantly expressed in many cancers, including glioblastoma. Methylation of DNA and histones provides a mode of epigenetic regulation, and cobalamin-dependent reactions link the redox state to methylation. Antagonists of dopamine receptor subtype 4 (D4 receptor) were recently shown to restrict glioblastoma stem cell growth by downregulating trophic signaling, resulting in inhibition of functional autophagy. In addition to stimulating glioblastoma stem cell growth, D4 receptors have the unique ability to catalyze cobalamin-dependent phospholipid methylation. Therefore, D4 receptors represent an important node in a molecular reflex pathway involving Nrf2 and cobalamin, operating in conjunction with redox status and methyl group donor availability. In this article, we describe the redox-related effects of Nrf2, cobalamin metabolism, and the D4 receptor on the regulation of the epigenetic state in glioblastoma.

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Objective To determine the role of metformin in regulating intracellular redox status and cell growth in prostate cancer cells Background : Prostate cancer is the second leading cause of cancer‐related death among males in the United States. Despite several advances in treatment options, there are several underlying challenges that affect prostate cancer therapy, including patient age, cancer resistance and undesirable side effects. Moreover, current treatment options focus on two or more cellular targets, such as, androgen synthesis, DNA repair enzymes and immune cells. Such cellular targets bypass the underlying supportive metabolic and molecular phenotypes that contribute to a cancer cell's ability to evade apoptosis, proliferate, and develop chemoresistance. Over the last decade, both preclinical and clinical studies have indicated the potential of metformin in prostate cancer therapy. Notably, these extensive studies demonstrated metformin's pleiotropic effects on several molecular and metabolic pathways such as androgen signaling, cell cycle and cellular bioenergetics, including its unique ability to activate the energy sensor 5 AMP activated kinase (AMPK). We previously demonstrated that metformin alters mitochondrial function in LNCaP prostate cancer cells resulting in elevated glycolysis. In light of this, we hypothesized that metformin induced oxidative stress, modulates prostate cancer cell survival, and is involved in its antiproliferative effects via the transsulfuration pathway. Methods : Using Seahorse XP extracellular analysis, we measured LNCaP prostate cancer cellular bioenergetics oxygen consumption rate (OCR) and extracellular acidification rate (ECAR) in the presence of metformin and SBI0206965 (an AMPK inhibitor). RT‐PCR, Liquid Chromatography/ Mass Spectrophotometry (LC/MS), Trypan Blue Exclusion and MTT assays were used to assess the effect of metformin on intracellular redox status and prostate cancer survival. Additionally, we also measured transsulfuration‐related enzymatic activities using an ELISA Assay. Results Metformin altered prostate cancer cellular bioenergetics resulting in decreased OCR and increased ECAR, reflecting oxidative phosphorylation and glycolytic activity, respectively. LC/MS analysis of metformin‐treated cells showed a significant reduction in GSH/GSSG ratio and metabolite levels associated with the transsulfuration pathway such as glutathione (GSH) and cystathionine (CYS). These low levels of GSH and CYS were consistent with an increase in the gene expression of transsulfuration related enzymes, cystathionine beta synthase (CBS) and cystathionine gamma‐lyase (CSE). Additionally, metformin increased the gene expression of the glutathione synthesis‐related enzyme γ‐glutamyl cysteine ligase (GCL), with no observable change in glutathione synthetase (GSS) gene expression. Notably, MTT and trypan blue exclusion assays indicated that metformin significantly decreased cell viability and had an anti‐proliferative effect on LNCaP prostate cancer cells. Conclusion :Metformi...