Black bean peptides inhibit glucose uptake in Caco-2 adenocarcinoma cells by blocking the expression and translocation pathway of glucose transporters

Luis Mojica, Diego A Luna-Vital, Elvira Gonzalez de Mejia, Luis Mojica, Diego A Luna-Vital, Elvira Gonzalez de Mejia

Abstract

The objective was to evaluate the effect of black bean protein fraction (PFRA), and its derived peptides on glucose uptake, SGLT1 and GLUT2 expression and translocation on Caco-2 cells. The effect of treatments was evaluated on glucose uptake, protein expression and localization and gene expression on Caco-2 cells. PFRA (10 mg/mL) lowered glucose uptake from 27.4% after 30 min to 33.9% after 180 min of treatment compared to untreated control (p < 0.05). All treatments lowered GLUT2 expression after 30 min of treatment compared to untreated control (31.4 to 48.6%, p < 0.05). Similarly, after 24 h of treatment, GLUT2 was decreased in all treatments (23.5% to 48.9%) (p < 0.05). SGLT1 protein expression decreased 18.3% for LSVSVL (100 μM) to 45.1% for PFRA (10 mg/mL) after 24 h. Immunofluorescence microscopy showed a decrease in expression and membrane translocation of GLUT2 and SGLT1 for all treatments compared to untreated control (p < 0.05). Relative gene expression of SLC2A2 (GLUT2) and SLC5A1 (SGLT1) was downregulated significantly up to two-fold change compared to the untreated control after 24 h treatment. Black bean protein fractions are an inexpensive, functional ingredient with significant biological potential to reduce glucose uptake and could be used as an adjuvant in the treatment of colorectal cancer.

Keywords: 2-NBDG PubChem CID: 6711157; 2-NBDG, 2-[N-(7-nitrobenz-2-oxa-1,3-diazol-4-yl)amino]-2-deoxy-d-glucose; A, alanine; AMPK, 5′ adenosine monophosphate-activated protein kinase; AU, arbitrary units; BPI, bean protein isolate; Black bean protein fraction; Colorectal cancer; E, glutamic acid; F, phenylalanine; GLUT2; GLUT2, glucose transporter 2; Glucose uptake; Glucose: PubChem CID: 10954115; I:K, lysine; L, leucine; N, asparagine; P FRA, protein fractions; P, proline; PHL, phloretin; PKC, protein kinase C II; Phloretin: PubChem CID: 4788; S, serine; SD, standard deviation; SGLT1; SGLT1, sodium-dependent glucose cotransporter 1; T, threonine; V, valine; WZB117, 3-fluoro-1,2-phenylene bis (3-hydroxybenzoate).

Figures

Graphical abstract
Graphical abstract
Fig. 1
Fig. 1
Inhibition kinetics of glucose uptake, using fluorescent glucose 2-NBDG, after treatment with either PFRA or derived peptides obtained from hydrolysis of black bean proteins. The data represent the mean ± SD of at least three independent replicates with consistent results. Different letters (a–d) indicate means that are significantly different (p 

Fig. 2

Effect of PFRA, and derived…

Fig. 2

Effect of PFRA, and derived peptides originally identified in black bean, on GLUT2,…

Fig. 2
Effect of PFRA, and derived peptides originally identified in black bean, on GLUT2, SGLT1, and GAPDH protein expression. A) Protein expression after 30 min treatment. B) Protein expression after 24 h treatment. The data represent the mean ± SE of at least three independent replicates with consistent results. Different letters (a,b,c,d) indicate means that are significantly different (p 

Fig. 3

Confocal laser scanning microscopy of…

Fig. 3

Confocal laser scanning microscopy of Caco-2 cells glucose transporters depicting two-dimensional fluorescence detection…

Fig. 3
Confocal laser scanning microscopy of Caco-2 cells glucose transporters depicting two-dimensional fluorescence detection and quantification. A–B) The nucleus (blue); GLUT2 (green) and SGLT1 (red) expression and translocation after 30 min and 24 h of glucose stimulation and treatment. C) Transversal view of cells either untreated or treated with PHL (phloretin, 100 μM) or PFRA (protein fractions, 10 mg/mL) indicating the location of the glucose transporters on the membrane. The glucose transporters intensity quantification as arbitrary units (AU) over the area (μm2) on the cell membrane and cytoplasm was measured. D) GLUT2, 30 min treatment. E) SGLT1, 30 min treatment. F) GUT2, 24 h treatment. G) SGLT1, 24 h treatment. The data represent the mean ± SD of four independent fields of view from two independent cellular replicates. *: Significantly, different (p < 0.05) compared to untreated control at the membrane level. ●: Significantly, different (p < 0.05) compared to untreated control at the cytoplasm level.

Fig. 4

mRNA relative expression presented as…

Fig. 4

mRNA relative expression presented as fold-change relative to untreated control and gene metabolic…

Fig. 4
mRNA relative expression presented as fold-change relative to untreated control and gene metabolic function. A) mRNA expression after 30 min. B) mRNA expression after 24 h. Data are expressed as the mean ± SD compared to untreated control. *: Significant fold change p 

Fig. 5

Molecular docking example of peptide…

Fig. 5

Molecular docking example of peptide ATNPLF interacting on the catalytic site of PKC…

Fig. 5
Molecular docking example of peptide ATNPLF interacting on the catalytic site of PKC and AMPK. A) A representative example of the best pose of peptide ATNPLF with PKC. B) PKC-ATNPLF catalytic site interactions are representing H-bond cloud. C) 2D PKC-ATNPLF catalytic site interactions. D) A representative example of the best pose of peptide ATNPLF with AMPK. E) AMPK-ATNPLF catalytic site interactions are representing H-bond cloud. F) 2D AMPK-ATNPLF catalytic site interactions.

Fig. 6

Proposed mechanism of action of…

Fig. 6

Proposed mechanism of action of bioactive peptides to reduce glucose uptake in colorectal…

Fig. 6
Proposed mechanism of action of bioactive peptides to reduce glucose uptake in colorectal cancer cells. Peptide fractions were able to block glucose transporters and proteins involved in their translocation pathway (PKC and AMPK) interacting with their active site. Peptide fraction and its derived peptides decreased protein and gene expressions of glucose transporters GLUT2 and SGLT1, promoting a decrease in cellular glucose uptake.
All figures (7)
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Cited by
References
    1. Luna-Vital D.A., de Mejía E.G., Dia V.P., Loarca-Piña G. Peptides in common bean fractions inhibit human colorectal cancer cells. Food Chem. 2014;157:347–355. - PubMed
    1. Luna-Vital D.A., Loarca-Piña G., Dia V.P., de Mejía E.G. Peptides extracted from common bean (Phaseolus vulgaris L.) non-digestible fraction caused differential gene expression of HCT116 and RKO human colorectal cancer cells. Food Res. Int. 2014;62:193–204.
    1. Luna-Vital D.A., de Mejía E.G., Loarca-Piña G. Selective mechanism of action of dietary peptides from common bean on HCT116 human colorectal cancer cells through loss of mitochondrial membrane potential and DNA damage. J. Funct. Foods. 2016;23:24–39.
    1. Mojica L., de Mejia E.G. Optimization of enzymatic production of anti-diabetic peptides from black bean (Phaseolus vulgaris L.) proteins, their characterization and biological potential. Food Funct. 2016;7(2):713–727. - PubMed
    1. Oseguera-Toledo M.E., de Mejía E.G., Reynoso-Camacho R., Cardador-Martínez A., Amaya-Llano S.L. Proteins and bioactive peptides. Nutrafoods. 2014;13(4):147–157.
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Fig. 2
Fig. 2
Effect of PFRA, and derived peptides originally identified in black bean, on GLUT2, SGLT1, and GAPDH protein expression. A) Protein expression after 30 min treatment. B) Protein expression after 24 h treatment. The data represent the mean ± SE of at least three independent replicates with consistent results. Different letters (a,b,c,d) indicate means that are significantly different (p 

Fig. 3

Confocal laser scanning microscopy of…

Fig. 3

Confocal laser scanning microscopy of Caco-2 cells glucose transporters depicting two-dimensional fluorescence detection…

Fig. 3
Confocal laser scanning microscopy of Caco-2 cells glucose transporters depicting two-dimensional fluorescence detection and quantification. A–B) The nucleus (blue); GLUT2 (green) and SGLT1 (red) expression and translocation after 30 min and 24 h of glucose stimulation and treatment. C) Transversal view of cells either untreated or treated with PHL (phloretin, 100 μM) or PFRA (protein fractions, 10 mg/mL) indicating the location of the glucose transporters on the membrane. The glucose transporters intensity quantification as arbitrary units (AU) over the area (μm2) on the cell membrane and cytoplasm was measured. D) GLUT2, 30 min treatment. E) SGLT1, 30 min treatment. F) GUT2, 24 h treatment. G) SGLT1, 24 h treatment. The data represent the mean ± SD of four independent fields of view from two independent cellular replicates. *: Significantly, different (p < 0.05) compared to untreated control at the membrane level. ●: Significantly, different (p < 0.05) compared to untreated control at the cytoplasm level.

Fig. 4

mRNA relative expression presented as…

Fig. 4

mRNA relative expression presented as fold-change relative to untreated control and gene metabolic…

Fig. 4
mRNA relative expression presented as fold-change relative to untreated control and gene metabolic function. A) mRNA expression after 30 min. B) mRNA expression after 24 h. Data are expressed as the mean ± SD compared to untreated control. *: Significant fold change p 

Fig. 5

Molecular docking example of peptide…

Fig. 5

Molecular docking example of peptide ATNPLF interacting on the catalytic site of PKC…

Fig. 5
Molecular docking example of peptide ATNPLF interacting on the catalytic site of PKC and AMPK. A) A representative example of the best pose of peptide ATNPLF with PKC. B) PKC-ATNPLF catalytic site interactions are representing H-bond cloud. C) 2D PKC-ATNPLF catalytic site interactions. D) A representative example of the best pose of peptide ATNPLF with AMPK. E) AMPK-ATNPLF catalytic site interactions are representing H-bond cloud. F) 2D AMPK-ATNPLF catalytic site interactions.

Fig. 6

Proposed mechanism of action of…

Fig. 6

Proposed mechanism of action of bioactive peptides to reduce glucose uptake in colorectal…

Fig. 6
Proposed mechanism of action of bioactive peptides to reduce glucose uptake in colorectal cancer cells. Peptide fractions were able to block glucose transporters and proteins involved in their translocation pathway (PKC and AMPK) interacting with their active site. Peptide fraction and its derived peptides decreased protein and gene expressions of glucose transporters GLUT2 and SGLT1, promoting a decrease in cellular glucose uptake.
All figures (7)
Similar articles
Cited by
References
    1. Luna-Vital D.A., de Mejía E.G., Dia V.P., Loarca-Piña G. Peptides in common bean fractions inhibit human colorectal cancer cells. Food Chem. 2014;157:347–355. - PubMed
    1. Luna-Vital D.A., Loarca-Piña G., Dia V.P., de Mejía E.G. Peptides extracted from common bean (Phaseolus vulgaris L.) non-digestible fraction caused differential gene expression of HCT116 and RKO human colorectal cancer cells. Food Res. Int. 2014;62:193–204.
    1. Luna-Vital D.A., de Mejía E.G., Loarca-Piña G. Selective mechanism of action of dietary peptides from common bean on HCT116 human colorectal cancer cells through loss of mitochondrial membrane potential and DNA damage. J. Funct. Foods. 2016;23:24–39.
    1. Mojica L., de Mejia E.G. Optimization of enzymatic production of anti-diabetic peptides from black bean (Phaseolus vulgaris L.) proteins, their characterization and biological potential. Food Funct. 2016;7(2):713–727. - PubMed
    1. Oseguera-Toledo M.E., de Mejía E.G., Reynoso-Camacho R., Cardador-Martínez A., Amaya-Llano S.L. Proteins and bioactive peptides. Nutrafoods. 2014;13(4):147–157.
Show all 45 references
[x]
Cite
Copy Download .nbib
Format: AMA APA MLA NLM
Fig. 3
Fig. 3
Confocal laser scanning microscopy of Caco-2 cells glucose transporters depicting two-dimensional fluorescence detection and quantification. A–B) The nucleus (blue); GLUT2 (green) and SGLT1 (red) expression and translocation after 30 min and 24 h of glucose stimulation and treatment. C) Transversal view of cells either untreated or treated with PHL (phloretin, 100 μM) or PFRA (protein fractions, 10 mg/mL) indicating the location of the glucose transporters on the membrane. The glucose transporters intensity quantification as arbitrary units (AU) over the area (μm2) on the cell membrane and cytoplasm was measured. D) GLUT2, 30 min treatment. E) SGLT1, 30 min treatment. F) GUT2, 24 h treatment. G) SGLT1, 24 h treatment. The data represent the mean ± SD of four independent fields of view from two independent cellular replicates. *: Significantly, different (p < 0.05) compared to untreated control at the membrane level. ●: Significantly, different (p < 0.05) compared to untreated control at the cytoplasm level.
Fig. 4
Fig. 4
mRNA relative expression presented as fold-change relative to untreated control and gene metabolic function. A) mRNA expression after 30 min. B) mRNA expression after 24 h. Data are expressed as the mean ± SD compared to untreated control. *: Significant fold change p 

Fig. 5

Molecular docking example of peptide…

Fig. 5

Molecular docking example of peptide ATNPLF interacting on the catalytic site of PKC…

Fig. 5
Molecular docking example of peptide ATNPLF interacting on the catalytic site of PKC and AMPK. A) A representative example of the best pose of peptide ATNPLF with PKC. B) PKC-ATNPLF catalytic site interactions are representing H-bond cloud. C) 2D PKC-ATNPLF catalytic site interactions. D) A representative example of the best pose of peptide ATNPLF with AMPK. E) AMPK-ATNPLF catalytic site interactions are representing H-bond cloud. F) 2D AMPK-ATNPLF catalytic site interactions.

Fig. 6

Proposed mechanism of action of…

Fig. 6

Proposed mechanism of action of bioactive peptides to reduce glucose uptake in colorectal…

Fig. 6
Proposed mechanism of action of bioactive peptides to reduce glucose uptake in colorectal cancer cells. Peptide fractions were able to block glucose transporters and proteins involved in their translocation pathway (PKC and AMPK) interacting with their active site. Peptide fraction and its derived peptides decreased protein and gene expressions of glucose transporters GLUT2 and SGLT1, promoting a decrease in cellular glucose uptake.
All figures (7)
Fig. 5
Fig. 5
Molecular docking example of peptide ATNPLF interacting on the catalytic site of PKC and AMPK. A) A representative example of the best pose of peptide ATNPLF with PKC. B) PKC-ATNPLF catalytic site interactions are representing H-bond cloud. C) 2D PKC-ATNPLF catalytic site interactions. D) A representative example of the best pose of peptide ATNPLF with AMPK. E) AMPK-ATNPLF catalytic site interactions are representing H-bond cloud. F) 2D AMPK-ATNPLF catalytic site interactions.
Fig. 6
Fig. 6
Proposed mechanism of action of bioactive peptides to reduce glucose uptake in colorectal cancer cells. Peptide fractions were able to block glucose transporters and proteins involved in their translocation pathway (PKC and AMPK) interacting with their active site. Peptide fraction and its derived peptides decreased protein and gene expressions of glucose transporters GLUT2 and SGLT1, promoting a decrease in cellular glucose uptake.

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