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Antimicrobial peptide FF/CAP18 induces apoptotic cell death in HCT116 colon cancer cells via changes in the metabolic profile.

Kuroda K, Fukuda T, Isogai H, Okumura K, Krstic-Demonacos M, Isogai E - Int. J. Oncol. (2015)

Bottom Line: We previously reported that cathelicidin-related or modified antimicrobial peptides, such as FF/CAP18, have antiproliferative effects on the squamous cell carcinoma cell line SAS-H1, and the colon carcinoma cell line HCT116.Purine metabolism, glycolysis, and the TCA cycle, were altered in FF/CAP18-treated cells in a dose-dependent manner.Our present study provides mechanistic insights into the anticancer effects of antimicrobial peptides that show great potential as new therapies for colon cancer.

View Article: PubMed Central - PubMed

Affiliation: Graduate School of Agricultural Science, Tohoku University, Aoba-ku, Sendai 981-8555, Japan.

ABSTRACT
Metabolic reprogramming is one of the hallmarks of cancer and can be targeted by therapeutic agents. We previously reported that cathelicidin-related or modified antimicrobial peptides, such as FF/CAP18, have antiproliferative effects on the squamous cell carcinoma cell line SAS-H1, and the colon carcinoma cell line HCT116. Although antimicrobial peptides have potential use in the development of new therapeutic strategies, their effects on the metabolism of cancer cells are poorly understood. Here, we investigated changes in the levels of metabolites in HCT116 cells caused by FF/CAP18, via capillary electrophoresis time-of-flight mass spectrometry (CE-TOFMS). Analysis of the 177 intracellular metabolites and 113 metabolites in conditioned medium that were detected by CE-TOFMS, revealed dramatic changes in the metabolic profile of HCT116 cells after treatment with FF/CAP18. The metabolic profile showed that the levels of most metabolites in the major metabolic pathways supported the rapid proliferation of cancer cells. Purine metabolism, glycolysis, and the TCA cycle, were altered in FF/CAP18-treated cells in a dose-dependent manner. Our present study provides mechanistic insights into the anticancer effects of antimicrobial peptides that show great potential as new therapies for colon cancer.

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Related in: MedlinePlus

Metabolome data map of all metabolic pathways for conditioned medium. Each bar represents the relative amount of a metabolite for control medium (blue), conditioned medium after culture of HCT116 cells (red) and conditioned medium after culture of HCT116 cells treated with FF/CAP18 at 10 μg/ml (green) or 40 μg/ml (yellow). All metabolite data are shown as the mean of triplicate samples ± standard deviation.
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f3-ijo-46-04-1516: Metabolome data map of all metabolic pathways for conditioned medium. Each bar represents the relative amount of a metabolite for control medium (blue), conditioned medium after culture of HCT116 cells (red) and conditioned medium after culture of HCT116 cells treated with FF/CAP18 at 10 μg/ml (green) or 40 μg/ml (yellow). All metabolite data are shown as the mean of triplicate samples ± standard deviation.

Mentions: The 177 intracellular metabolites and 113 metabolites in conditioned medium were detected as peaks by CE-TOFMS, and mapped onto metabolic pathways for ease of viewing, as shown in Fig. 2 (cells) and Fig. 3 (conditioned medium). Overall trends of the intracellular metabolomic changes in HCT116 cells treated with FF/CAP18 and non-treated cells were analyzed by Euclidean-distance-based HCA, and the results are presented as a heat map (Fig. 4). The metabolomic profile of HCT116 cells treated with 10 μg/ml FF/CAP18 showed high values for the metabolites in cluster 2, including amino acids, and tricarboxylic acid (TCA) cycle intermediates. In contrast, the metabolomic profile of HCT116 cells treated with 40 μg/ml FF/CAP18 was reversed in comparison to the profile for treatment with 10 μg/ml FF/CAP18. We also confirmed that the metabolomic profiles of HCT116 cells treated with FF/CAP18 at 10 or 40 μg/ml were reversed for metabolites in cluster 1, including nucleotides and nucleosides. These trends were made even clearer from the results of the PCA of metabolome data for HCT116 cells treated with FF/CAP18 (Fig. 5). The concentration of FF/CAP18 was reflected in principal component 1; principal component 2 demonstrated the difference between treatment and non-treatment of cells with FF/CAP18. Therefore, treatment with FF/CAP18 exerted a dramatic change on the metabolism of HCT116 cells, and that change depended on the concentration of FF/CAP18.


Antimicrobial peptide FF/CAP18 induces apoptotic cell death in HCT116 colon cancer cells via changes in the metabolic profile.

Kuroda K, Fukuda T, Isogai H, Okumura K, Krstic-Demonacos M, Isogai E - Int. J. Oncol. (2015)

Metabolome data map of all metabolic pathways for conditioned medium. Each bar represents the relative amount of a metabolite for control medium (blue), conditioned medium after culture of HCT116 cells (red) and conditioned medium after culture of HCT116 cells treated with FF/CAP18 at 10 μg/ml (green) or 40 μg/ml (yellow). All metabolite data are shown as the mean of triplicate samples ± standard deviation.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4356497&req=5

f3-ijo-46-04-1516: Metabolome data map of all metabolic pathways for conditioned medium. Each bar represents the relative amount of a metabolite for control medium (blue), conditioned medium after culture of HCT116 cells (red) and conditioned medium after culture of HCT116 cells treated with FF/CAP18 at 10 μg/ml (green) or 40 μg/ml (yellow). All metabolite data are shown as the mean of triplicate samples ± standard deviation.
Mentions: The 177 intracellular metabolites and 113 metabolites in conditioned medium were detected as peaks by CE-TOFMS, and mapped onto metabolic pathways for ease of viewing, as shown in Fig. 2 (cells) and Fig. 3 (conditioned medium). Overall trends of the intracellular metabolomic changes in HCT116 cells treated with FF/CAP18 and non-treated cells were analyzed by Euclidean-distance-based HCA, and the results are presented as a heat map (Fig. 4). The metabolomic profile of HCT116 cells treated with 10 μg/ml FF/CAP18 showed high values for the metabolites in cluster 2, including amino acids, and tricarboxylic acid (TCA) cycle intermediates. In contrast, the metabolomic profile of HCT116 cells treated with 40 μg/ml FF/CAP18 was reversed in comparison to the profile for treatment with 10 μg/ml FF/CAP18. We also confirmed that the metabolomic profiles of HCT116 cells treated with FF/CAP18 at 10 or 40 μg/ml were reversed for metabolites in cluster 1, including nucleotides and nucleosides. These trends were made even clearer from the results of the PCA of metabolome data for HCT116 cells treated with FF/CAP18 (Fig. 5). The concentration of FF/CAP18 was reflected in principal component 1; principal component 2 demonstrated the difference between treatment and non-treatment of cells with FF/CAP18. Therefore, treatment with FF/CAP18 exerted a dramatic change on the metabolism of HCT116 cells, and that change depended on the concentration of FF/CAP18.

Bottom Line: We previously reported that cathelicidin-related or modified antimicrobial peptides, such as FF/CAP18, have antiproliferative effects on the squamous cell carcinoma cell line SAS-H1, and the colon carcinoma cell line HCT116.Purine metabolism, glycolysis, and the TCA cycle, were altered in FF/CAP18-treated cells in a dose-dependent manner.Our present study provides mechanistic insights into the anticancer effects of antimicrobial peptides that show great potential as new therapies for colon cancer.

View Article: PubMed Central - PubMed

Affiliation: Graduate School of Agricultural Science, Tohoku University, Aoba-ku, Sendai 981-8555, Japan.

ABSTRACT
Metabolic reprogramming is one of the hallmarks of cancer and can be targeted by therapeutic agents. We previously reported that cathelicidin-related or modified antimicrobial peptides, such as FF/CAP18, have antiproliferative effects on the squamous cell carcinoma cell line SAS-H1, and the colon carcinoma cell line HCT116. Although antimicrobial peptides have potential use in the development of new therapeutic strategies, their effects on the metabolism of cancer cells are poorly understood. Here, we investigated changes in the levels of metabolites in HCT116 cells caused by FF/CAP18, via capillary electrophoresis time-of-flight mass spectrometry (CE-TOFMS). Analysis of the 177 intracellular metabolites and 113 metabolites in conditioned medium that were detected by CE-TOFMS, revealed dramatic changes in the metabolic profile of HCT116 cells after treatment with FF/CAP18. The metabolic profile showed that the levels of most metabolites in the major metabolic pathways supported the rapid proliferation of cancer cells. Purine metabolism, glycolysis, and the TCA cycle, were altered in FF/CAP18-treated cells in a dose-dependent manner. Our present study provides mechanistic insights into the anticancer effects of antimicrobial peptides that show great potential as new therapies for colon cancer.

Show MeSH
Related in: MedlinePlus