One-Carbon Metabolism in Prostate Cancer: The Role of Androgen Signaling

Abstract

Cancer cell metabolism differs significantly from the metabolism of non-transformed cells. This altered metabolic reprogramming mediates changes in the uptake and use of nutrients that permit high rates of proliferation, growth, and survival. The androgen receptor (AR) plays an essential role in the establishment and progression of prostate cancer (PCa), and in the metabolic adaptation that takes place during this progression. In its role as a transcription factor, the AR directly affects the expression of several effectors and regulators of essential catabolic and biosynthetic pathways. Indirectly, as a modulator of the one-carbon metabolism, the AR can affect epigenetic processes, DNA metabolism, and redox balance, all of which are important factors in tumorigenesis. In this review, we focus on the role of AR-signaling on one-carbon metabolism in tumorigenesis. Clinical implications of one-carbon metabolism and AR-targeted therapies for PCa are discussed in this context.

Life-threatening course in coronavirus disease 2019 (COVID-19): Is there a link to methylenetetrahydrofolic acid reductase (MTHFR) polymorphism and hyperhomocysteinemia?

“…There is also a relationship of MTHFR polymorphisms and reduced levels of glutathione as the folate cycle, the methionine cycle and the transsulfuration pathway are intricably linked [17] . S-adenosyl-methionine levels are lowered in states of low MTHFR activity which results in decreased stimulation of cystathionine beta-synthase (CBS), the enzyme that shuttles homocysteine into the transsulfuration pathway that ultimately leads to the synthesis of glutathione [17] .…”

Androgen Receptor Signaling and Metabolic and Cellular Plasticity During Progression to Castration Resistant Prostate Cancer

“…AR regulates one-carbon metabolism network consisting of the two folate cycle pathways (DHFR, GNMT, SARDH), and methionine cycle (MAT, AHCY) which interact with trans-sulfuration pathway (CBS, CTH) and polyamine synthesis (ODC1, AMD1) ( 81 – 83 ). The methionine cycle contributes to the formation of S -adenosyl-methionine (SAM), the universal methyl donor for protein and DNA methyltransferase reactions( 84 ).…”

“…The methionine cycle contributes to the formation of S -adenosyl-methionine (SAM), the universal methyl donor for protein and DNA methyltransferase reactions( 84 ). Thus, this metabolism may contribute to AR-driven malignant progression by promoting DNA synthesis and changing DNA and histone methylation status ( 81 ). As discussed below, availability of SAM determines neuroendocrine PCa (NEPC) status which is AR independent ( 85 ).…”

In Utero One‐Carbon Metabolism Interplay and Metabolic Syndrome in Cardiovascular Disease Risk Reduction

“…In the folate cycle, folic acid serves as a precursor for generation of 5,10‐methylene THF, which is in turn utilized for DNA synthesis or methylation pathway via a series of metabolic reactions that yield methionine with the involvement of vitamin B 12 and betaine (choline derivative). Adapted from Corbin and Ruiz‐Echevarria . SAM, S‐adenosylmethionine; SAH, S‐adenosyhomocysteine; MT, Methionine transferases; MAT, Methionine adenosyltransferase, SAHH, S‐adenosylhomocysteine hydrolase; BHMT, Betaine‐homocysteine S‐methyltransferase; THF, tetrahydrofolate; DHF, Dihydrofolate; DHFR, Dihydrofolate reductase; SHMT, Serine hydroxymethyltransferase; MTHFR, Methylenetetrahydrofolate Reductase; MS, Methionine synthase; CBS, Cystathionine β synthase.…”