Role of S-adenosylmethionine cycle in carcinogenesis

Murín, Radovan; Vidomanová, Eva; Kowtharapu, Bhavani S.; Hatok, Jozef; Dobrota, Dušan

doi:10.4149/gpb_2017031

Cited by 20 publications

(14 citation statements)

References 54 publications

(66 reference statements)

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“…SAM is also metabolized through the methionine salvage pathway, wherein SAM is first decarboxylated and then recycled with the by guest on October 30, 2020 http://www.jbc.org/ Downloaded from release of methionine, adenosine and polyamines (29). In the deregulated MTHFR mutant, we observed a 2.5 fold increase in the amount of spermine suggesting that the pathway is indeed active in the mutant.This possibly also explains why arginine, which is a precursor for spermine, is also observed at significantly lower levels in the deregulated mutant.…”

Section: Discussionmentioning

confidence: 70%

Allosteric inhibition of MTHFR prevents futile SAM cycling and maintains nucleotide pools in one-carbon metabolism

Bhatia

Thakur

Suyal

et al. 2020

Journal of Biological Chemistry

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Methylenetetrahydrofolate reductase (MTHFR) links the folate cycle to the methionine cycle in one-carbon metabolism. The enzyme is known to be allosterically inhibited by S-adenosyl methionine (SAM) for decades, but the importance of this regulatory control to one carbon metabolism has never been adequately understood. To shed light on this issue, we exchanged selected amino acid residues in a highly conserved stretch within the regulatory region of yeast MTHFR to create a series of feedback-insensitive, deregulated mutants. These were exploited to investigate the impact of defective allosteric regulation on one carbon metabolism. We observed a strong growth defect in the presence of methionine. Biochemical and metabolite analysis revealed that both the folate and methionine cycles were affected in these mutants, as was the transulfuration pathway, leading also to a disruption in redox homeostasis. The major consequences, however, appeared to be in the depletion of nucleotides. 13C isotope labelling and metabolic studies revealed that the deregulated MTHFR cells undergo continuous transmethylation of homocysteine by methyltetrahydrofolate (CH3THF) to form methionine. This reaction also drives SAM formation and further depletes ATP reserves. SAM was then cycled back to methionine, leading to futile cycles of SAM synthesis and recycling, and explaining the necessity for MTHFR to be regulated by SAM. The study has yielded valuable new insights into the regulation of one carbon metabolism, and the mutants appear as powerful new tools to further dissect out the intersection of one carbon metabolism with various pathways both in yeasts and in humans.

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Section: Discussionmentioning

confidence: 70%

Allosteric inhibition of MTHFR prevents futile SAM cycling and maintains nucleotide pools in one-carbon metabolism

Bhatia

Thakur

Suyal

et al. 2020

Journal of Biological Chemistry

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“…MAT1A belongs to a family of methyltransferases that contribute to methylation of a variety of molecules including DNA and histones, via synthesis of SAM [18]. In cancer research, MAT1A has been mostly described in the context of hepatocellular carcinoma (HCC), where it was previously shown that a switch in gene expression from MAT1A to MAT2A (M1-M2 switch) promoted cancer invasion and metastasis.…”

Section: Discussionmentioning

confidence: 99%

Methionine Adenosyltransferase 1a (MAT1A) Enhances Cell Survival During Chemotherapy Treatment and is Associated with Drug Resistance in Bladder Cancer PDX Mice

Martin

Hum

Sebastian

et al. 2019

IJMS

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Bladder cancer is among the top ten most common cancers, with about ~380,000 new cases and ~150,000 deaths per year worldwide. Tumor relapse following chemotherapy treatment has long been a significant challenge towards completely curing cancer. We have utilized a patient-derived bladder cancer xenograft (PDX) platform to characterize molecular mechanisms that contribute to relapse following drug treatment in advanced bladder cancer. Transcriptomic profiling of bladder cancer xenograft tumors by RNA-sequencing analysis, before and after relapse, following a 21-day cisplatin/gemcitabine drug treatment regimen identified methionine adenosyltransferase 1a (MAT1A) as one of the significantly upregulated genes following drug treatment. Survey of patient tumor sections confirmed elevated levels of MAT1A in individuals who received chemotherapy. Overexpression of MAT1A in 5637 bladder cancer cells increased tolerance to gemcitabine and stalled cell proliferation rates, suggesting MAT1A upregulation as a potential mechanism by which bladder cancer cells persist in a quiescent state to evade chemotherapy.

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“…The high extracellular ATP concentration characteristic of neoplastic cells is also related to the elevated presence of exADO, according to the expression and activity of various ectonucleotidases. In this context, the nucleoside ADO has been recognized as a pro-tumoral factor [128]. For example, in non-small cell cancer tissues and cancer-associated fibroblast, antagonists for A2AR (ZM241385 and SCH5826) inhibited cellular proliferation and the human tumor xenograft in mice [129].…”

Section: Warburg Effect and Purinergic Signalingmentioning

confidence: 99%

Purinergic Signaling in the Hallmarks of Cancer

Campos-Contreras

Dı́az-Muñoz

Vázquez‐Cuevas

2020

Cells

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Cancer is a complex expression of an altered state of cellular differentiation associated with severe clinical repercussions. The effort to characterize this pathological entity to understand its underlying mechanisms and visualize potential therapeutic strategies has been constant. In this context, some cellular (enhanced duplication, immunological evasion), metabolic (aerobic glycolysis, failure in DNA repair mechanisms) and physiological (circadian disruption) parameters have been considered as cancer hallmarks. The list of these hallmarks has been growing in recent years, since it has been demonstrated that various physiological systems misfunction in well-characterized ways upon the onset and establishment of the carcinogenic process. This is the case with the purinergic system, a signaling pathway formed by nucleotides/nucleosides (mainly adenosine triphosphate (ATP), adenosine (ADO) and uridine triphosphate (UTP)) with their corresponding membrane receptors and defined transduction mechanisms. The dynamic equilibrium between ATP and ADO, which is accomplished by the presence and regulation of a set of ectonucleotidases, defines the pro-carcinogenic or anti-cancerous final outline in tumors and cancer cell lines. So far, the purinergic system has been recognized as a potential therapeutic target in cancerous and tumoral ailments.

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Role of S-adenosylmethionine cycle in carcinogenesis

Cited by 20 publications

References 54 publications

Allosteric inhibition of MTHFR prevents futile SAM cycling and maintains nucleotide pools in one-carbon metabolism

Allosteric inhibition of MTHFR prevents futile SAM cycling and maintains nucleotide pools in one-carbon metabolism

Methionine Adenosyltransferase 1a (MAT1A) Enhances Cell Survival During Chemotherapy Treatment and is Associated with Drug Resistance in Bladder Cancer PDX Mice

Purinergic Signaling in the Hallmarks of Cancer

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