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The Dysregulation of Polyamine Metabolism in Colorectal Cancer Is Associated with Overexpression of c-Myc and C/EBPβ rather than Enterotoxigenic Bacteroides fragilis Infection.

Snezhkina AV, Krasnov GS, Lipatova AV, Sadritdinova AF, Kardymon OL, Fedorova MS, Melnikova NV, Stepanov OA, Zaretsky AR, Kaprin AD, Alekseev BY, Dmitriev AA, Kudryavtseva AV - Oxid Med Cell Longev (2016)

Bottom Line: We found no statistically significant associations between them.We found that two mediators of metabolic reprogramming, inflammation, and cell proliferation c-Myc and C/EBPβ may serve as regulators of polyamine metabolism genes (SMOX, AZIN1, MTAP, SRM, ODC1, AMD1, and AGMAT) as they are overexpressed in tumors, have binding site according to ENCODE ChIP-Seq data, and demonstrate strong coexpression with their targets.Thus, increased polyamine metabolism in CRC could be driven by c-Myc and C/EBPβ rather than ETBF infection.

View Article: PubMed Central - PubMed

Affiliation: Engelhardt Institute of Molecular Biology, Russian Academy of Sciences, Moscow 119991, Russia.

ABSTRACT
Colorectal cancer is one of the most common cancers in the world. It is well known that the chronic inflammation can promote the progression of colorectal cancer (CRC). Recently, a number of studies revealed a potential association between colorectal inflammation, cancer progression, and infection caused by enterotoxigenic Bacteroides fragilis (ETBF). Bacterial enterotoxin activates spermine oxidase (SMO), which produces spermidine and H2O2 as byproducts of polyamine catabolism, which, in turn, enhances inflammation and tissue injury. Using qPCR analysis, we estimated the expression of SMOX gene and ETBF colonization in CRC patients. We found no statistically significant associations between them. Then we selected genes involved in polyamine metabolism, metabolic reprogramming, and inflammation regulation and estimated their expression in CRC. We observed overexpression of SMOX, ODC1, SRM, SMS, MTAP, c-Myc, C/EBPβ (CREBP), and other genes. We found that two mediators of metabolic reprogramming, inflammation, and cell proliferation c-Myc and C/EBPβ may serve as regulators of polyamine metabolism genes (SMOX, AZIN1, MTAP, SRM, ODC1, AMD1, and AGMAT) as they are overexpressed in tumors, have binding site according to ENCODE ChIP-Seq data, and demonstrate strong coexpression with their targets. Thus, increased polyamine metabolism in CRC could be driven by c-Myc and C/EBPβ rather than ETBF infection.

No MeSH data available.


Related in: MedlinePlus

Classic path of polyamine metabolism consists of the following: (1) arginine is converted to ornithine through the action of ARG (arginase) in the urea cycle; (2) putrescine is formed from the reaction of ornithine decarboxylation catalyzed by ODC1 (ornithine decarboxylase-1). OAZ can bind to ODC1 to form OAZ-ODC1 complex and subsequently reduce polyamine synthesis. AZIN1 (antizyme inhibitor-1) brakes the ODC1-OAZ complex and liberates ODC1; (3) AMD1 (S-adenosylmethionine decarboxylase) decarboxylates S-adenosylmethionine (SAM) to decarboxylated SAM (dcSAM); (4) dcSAM provides aminopropyl groups to putrescine to produce spermidine by spermidine synthase (SRM) and spermine by spermine synthase (SMS). MTA (methylthioadenosine) is generated as a byproduct. Spermine can be recycled back to spermidine directly by spermine oxidase (SMOX). Spermine and spermidine can be recycled to spermidine and putrescine by spermidine/spermine-N1-acetyltransferase (SAT1) followed by oxidation by polyamine oxidase (PAOX) [101]. MTA can be processed to the methionine: MTA phosphorylase (MTAP) catalyzes the cleavage of MTA yielding 5-methylthioribose-1-phosphate (MTRu-P), which is further metabolized to DHKMP (1,2-dihydro-3-keto-5-methylthiopentene). ADI (acireductone dioxygenase) catalyzes DHKMP to 2-oxo-4-methylthiobutyrate (KMTB) and transamination of KMTB results in formation of methionine [102–104].
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fig4: Classic path of polyamine metabolism consists of the following: (1) arginine is converted to ornithine through the action of ARG (arginase) in the urea cycle; (2) putrescine is formed from the reaction of ornithine decarboxylation catalyzed by ODC1 (ornithine decarboxylase-1). OAZ can bind to ODC1 to form OAZ-ODC1 complex and subsequently reduce polyamine synthesis. AZIN1 (antizyme inhibitor-1) brakes the ODC1-OAZ complex and liberates ODC1; (3) AMD1 (S-adenosylmethionine decarboxylase) decarboxylates S-adenosylmethionine (SAM) to decarboxylated SAM (dcSAM); (4) dcSAM provides aminopropyl groups to putrescine to produce spermidine by spermidine synthase (SRM) and spermine by spermine synthase (SMS). MTA (methylthioadenosine) is generated as a byproduct. Spermine can be recycled back to spermidine directly by spermine oxidase (SMOX). Spermine and spermidine can be recycled to spermidine and putrescine by spermidine/spermine-N1-acetyltransferase (SAT1) followed by oxidation by polyamine oxidase (PAOX) [101]. MTA can be processed to the methionine: MTA phosphorylase (MTAP) catalyzes the cleavage of MTA yielding 5-methylthioribose-1-phosphate (MTRu-P), which is further metabolized to DHKMP (1,2-dihydro-3-keto-5-methylthiopentene). ADI (acireductone dioxygenase) catalyzes DHKMP to 2-oxo-4-methylthiobutyrate (KMTB) and transamination of KMTB results in formation of methionine [102–104].

Mentions: Polyamines are organic cations, which are essential for cell proliferation and growth, and their levels are frequently altered in many human tumors [69, 70]. Polyamines have also been shown to play an important role in inflammation-induced carcinogenesis [71]. Intracellular polyamine metabolism occurs via two pathways: classical and alternate (Figure 4). Polyamines (putrescine, spermidine, and spermine) are synthesized by mammalian cells, while agmatine is produced only by plants and bacteria, including intestinal microbial flora [72–74]. L-arginine carboxylase (ADC), found only in nonmammals, catalyzes a reaction of decarboxylation of L-arginine to agmatine [72, 75]. The latter is further hydrolyzed to putrescine and urea by agmatinase, which is encoded by AGMAT gene. Recent reports also supposed that different pathogens, such as viruses and bacteria, could upregulate agmatinase at mRNA and protein levels, thereby inducing polyamine synthesis [76, 77].


The Dysregulation of Polyamine Metabolism in Colorectal Cancer Is Associated with Overexpression of c-Myc and C/EBPβ rather than Enterotoxigenic Bacteroides fragilis Infection.

Snezhkina AV, Krasnov GS, Lipatova AV, Sadritdinova AF, Kardymon OL, Fedorova MS, Melnikova NV, Stepanov OA, Zaretsky AR, Kaprin AD, Alekseev BY, Dmitriev AA, Kudryavtseva AV - Oxid Med Cell Longev (2016)

Classic path of polyamine metabolism consists of the following: (1) arginine is converted to ornithine through the action of ARG (arginase) in the urea cycle; (2) putrescine is formed from the reaction of ornithine decarboxylation catalyzed by ODC1 (ornithine decarboxylase-1). OAZ can bind to ODC1 to form OAZ-ODC1 complex and subsequently reduce polyamine synthesis. AZIN1 (antizyme inhibitor-1) brakes the ODC1-OAZ complex and liberates ODC1; (3) AMD1 (S-adenosylmethionine decarboxylase) decarboxylates S-adenosylmethionine (SAM) to decarboxylated SAM (dcSAM); (4) dcSAM provides aminopropyl groups to putrescine to produce spermidine by spermidine synthase (SRM) and spermine by spermine synthase (SMS). MTA (methylthioadenosine) is generated as a byproduct. Spermine can be recycled back to spermidine directly by spermine oxidase (SMOX). Spermine and spermidine can be recycled to spermidine and putrescine by spermidine/spermine-N1-acetyltransferase (SAT1) followed by oxidation by polyamine oxidase (PAOX) [101]. MTA can be processed to the methionine: MTA phosphorylase (MTAP) catalyzes the cleavage of MTA yielding 5-methylthioribose-1-phosphate (MTRu-P), which is further metabolized to DHKMP (1,2-dihydro-3-keto-5-methylthiopentene). ADI (acireductone dioxygenase) catalyzes DHKMP to 2-oxo-4-methylthiobutyrate (KMTB) and transamination of KMTB results in formation of methionine [102–104].
© Copyright Policy - open-access
Related In: Results  -  Collection

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getmorefigures.php?uid=PMC4940579&req=5

fig4: Classic path of polyamine metabolism consists of the following: (1) arginine is converted to ornithine through the action of ARG (arginase) in the urea cycle; (2) putrescine is formed from the reaction of ornithine decarboxylation catalyzed by ODC1 (ornithine decarboxylase-1). OAZ can bind to ODC1 to form OAZ-ODC1 complex and subsequently reduce polyamine synthesis. AZIN1 (antizyme inhibitor-1) brakes the ODC1-OAZ complex and liberates ODC1; (3) AMD1 (S-adenosylmethionine decarboxylase) decarboxylates S-adenosylmethionine (SAM) to decarboxylated SAM (dcSAM); (4) dcSAM provides aminopropyl groups to putrescine to produce spermidine by spermidine synthase (SRM) and spermine by spermine synthase (SMS). MTA (methylthioadenosine) is generated as a byproduct. Spermine can be recycled back to spermidine directly by spermine oxidase (SMOX). Spermine and spermidine can be recycled to spermidine and putrescine by spermidine/spermine-N1-acetyltransferase (SAT1) followed by oxidation by polyamine oxidase (PAOX) [101]. MTA can be processed to the methionine: MTA phosphorylase (MTAP) catalyzes the cleavage of MTA yielding 5-methylthioribose-1-phosphate (MTRu-P), which is further metabolized to DHKMP (1,2-dihydro-3-keto-5-methylthiopentene). ADI (acireductone dioxygenase) catalyzes DHKMP to 2-oxo-4-methylthiobutyrate (KMTB) and transamination of KMTB results in formation of methionine [102–104].
Mentions: Polyamines are organic cations, which are essential for cell proliferation and growth, and their levels are frequently altered in many human tumors [69, 70]. Polyamines have also been shown to play an important role in inflammation-induced carcinogenesis [71]. Intracellular polyamine metabolism occurs via two pathways: classical and alternate (Figure 4). Polyamines (putrescine, spermidine, and spermine) are synthesized by mammalian cells, while agmatine is produced only by plants and bacteria, including intestinal microbial flora [72–74]. L-arginine carboxylase (ADC), found only in nonmammals, catalyzes a reaction of decarboxylation of L-arginine to agmatine [72, 75]. The latter is further hydrolyzed to putrescine and urea by agmatinase, which is encoded by AGMAT gene. Recent reports also supposed that different pathogens, such as viruses and bacteria, could upregulate agmatinase at mRNA and protein levels, thereby inducing polyamine synthesis [76, 77].

Bottom Line: We found no statistically significant associations between them.We found that two mediators of metabolic reprogramming, inflammation, and cell proliferation c-Myc and C/EBPβ may serve as regulators of polyamine metabolism genes (SMOX, AZIN1, MTAP, SRM, ODC1, AMD1, and AGMAT) as they are overexpressed in tumors, have binding site according to ENCODE ChIP-Seq data, and demonstrate strong coexpression with their targets.Thus, increased polyamine metabolism in CRC could be driven by c-Myc and C/EBPβ rather than ETBF infection.

View Article: PubMed Central - PubMed

Affiliation: Engelhardt Institute of Molecular Biology, Russian Academy of Sciences, Moscow 119991, Russia.

ABSTRACT
Colorectal cancer is one of the most common cancers in the world. It is well known that the chronic inflammation can promote the progression of colorectal cancer (CRC). Recently, a number of studies revealed a potential association between colorectal inflammation, cancer progression, and infection caused by enterotoxigenic Bacteroides fragilis (ETBF). Bacterial enterotoxin activates spermine oxidase (SMO), which produces spermidine and H2O2 as byproducts of polyamine catabolism, which, in turn, enhances inflammation and tissue injury. Using qPCR analysis, we estimated the expression of SMOX gene and ETBF colonization in CRC patients. We found no statistically significant associations between them. Then we selected genes involved in polyamine metabolism, metabolic reprogramming, and inflammation regulation and estimated their expression in CRC. We observed overexpression of SMOX, ODC1, SRM, SMS, MTAP, c-Myc, C/EBPβ (CREBP), and other genes. We found that two mediators of metabolic reprogramming, inflammation, and cell proliferation c-Myc and C/EBPβ may serve as regulators of polyamine metabolism genes (SMOX, AZIN1, MTAP, SRM, ODC1, AMD1, and AGMAT) as they are overexpressed in tumors, have binding site according to ENCODE ChIP-Seq data, and demonstrate strong coexpression with their targets. Thus, increased polyamine metabolism in CRC could be driven by c-Myc and C/EBPβ rather than ETBF infection.

No MeSH data available.


Related in: MedlinePlus