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Opposing effects of butyrate and bile acids on apoptosis of human colon adenoma cells: differential activation of PKC and MAP kinases.

McMillan L, Butcher SK, Pongracz J, Lord JM - Br. J. Cancer (2003)

Bottom Line: We have shown previously that the proapoptotic effects of butyrate on AA/C1 human adenoma cells were reduced in the presence of bile acids.Butyrate-induced apoptosis was reduced by inhibitors of PKC-delta (Rottlerin), p38 MAP kinase (SB202190) and caspase 3 (DEVD-fmk), whereas the proliferative/survival effects of UDCA were blocked by inhibitors of PKC-alpha (Gö6976) and MEK 1 (PD98059).The effects of butyrate and bile acids are therefore mediated by the differential activation of signalling pathways that are known to regulate apoptosis.

View Article: PubMed Central - PubMed

Affiliation: Department of Immunology, The Medical School, Birmingham University, UK.

ABSTRACT
Butyrate, produced in the colon by fermentation of dietary fibre, induces apoptosis in colon adenoma and cancer cell lines, which may contribute to protection against colorectal cancer. However, butyrate is present in the colon along with other dietary factors, including unconjugated bile acids, which are tumour promoters. We have shown previously that the proapoptotic effects of butyrate on AA/C1 human adenoma cells were reduced in the presence of bile acids. To determine the cellular basis of this interaction, we examined the effects of butyrate and the secondary bile acid ursodeoxycholic acid (UDCA) on signalling pathways known to regulate apoptosis using AA/C1 cells. Butyrate activated PKC-delta and p38 MAP (mitogen-activated protein) kinase, whereas UDCA activated PKC-alpha and p42/44 MAP kinase. Butyrate treatment also resulted in the caspase-3-mediated proteolysis of PKC-delta. Butyrate-induced apoptosis was reduced by inhibitors of PKC-delta (Rottlerin), p38 MAP kinase (SB202190) and caspase 3 (DEVD-fmk), whereas the proliferative/survival effects of UDCA were blocked by inhibitors of PKC-alpha (Gö6976) and MEK 1 (PD98059). The effects of butyrate and bile acids are therefore mediated by the differential activation of signalling pathways that are known to regulate apoptosis.

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Effect of butyrate and UDCA on p38 and p42/44 MAP kinase activity. AA/C1 cells treated with 6 mM butyrate or 10 μM UDCA for 24 h. Cells were examined for the presence of activated, phosphorylated p38 MAP kinase (pP38) and p42/44 MAP kinase (pP42/44) by Western blotting. PD98059 was also included with UDCA treatments (lane 5) to inhibit activation of p42/44 MAP kinase by MEK1, and SB202190 was included with butyrate treatments (lane 3) to inhibit p38 MAP kinase. Equal loading of gels was confirmed using an antibody to total P38 and P42/44 MAP kinase. The blot shown is a representative of three similar experiments performed.
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fig3: Effect of butyrate and UDCA on p38 and p42/44 MAP kinase activity. AA/C1 cells treated with 6 mM butyrate or 10 μM UDCA for 24 h. Cells were examined for the presence of activated, phosphorylated p38 MAP kinase (pP38) and p42/44 MAP kinase (pP42/44) by Western blotting. PD98059 was also included with UDCA treatments (lane 5) to inhibit activation of p42/44 MAP kinase by MEK1, and SB202190 was included with butyrate treatments (lane 3) to inhibit p38 MAP kinase. Equal loading of gels was confirmed using an antibody to total P38 and P42/44 MAP kinase. The blot shown is a representative of three similar experiments performed.

Mentions: Butyrate (6 mM) induced activation of p38 MAP kinase in AA/C1 cells, indicated by an increase in the level of phosphorylated p38 MAP kinase, but did not induce activation of p42/44 MAP kinase (Figure 3Figure 3


Opposing effects of butyrate and bile acids on apoptosis of human colon adenoma cells: differential activation of PKC and MAP kinases.

McMillan L, Butcher SK, Pongracz J, Lord JM - Br. J. Cancer (2003)

Effect of butyrate and UDCA on p38 and p42/44 MAP kinase activity. AA/C1 cells treated with 6 mM butyrate or 10 μM UDCA for 24 h. Cells were examined for the presence of activated, phosphorylated p38 MAP kinase (pP38) and p42/44 MAP kinase (pP42/44) by Western blotting. PD98059 was also included with UDCA treatments (lane 5) to inhibit activation of p42/44 MAP kinase by MEK1, and SB202190 was included with butyrate treatments (lane 3) to inhibit p38 MAP kinase. Equal loading of gels was confirmed using an antibody to total P38 and P42/44 MAP kinase. The blot shown is a representative of three similar experiments performed.
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Related In: Results  -  Collection

Show All Figures
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fig3: Effect of butyrate and UDCA on p38 and p42/44 MAP kinase activity. AA/C1 cells treated with 6 mM butyrate or 10 μM UDCA for 24 h. Cells were examined for the presence of activated, phosphorylated p38 MAP kinase (pP38) and p42/44 MAP kinase (pP42/44) by Western blotting. PD98059 was also included with UDCA treatments (lane 5) to inhibit activation of p42/44 MAP kinase by MEK1, and SB202190 was included with butyrate treatments (lane 3) to inhibit p38 MAP kinase. Equal loading of gels was confirmed using an antibody to total P38 and P42/44 MAP kinase. The blot shown is a representative of three similar experiments performed.
Mentions: Butyrate (6 mM) induced activation of p38 MAP kinase in AA/C1 cells, indicated by an increase in the level of phosphorylated p38 MAP kinase, but did not induce activation of p42/44 MAP kinase (Figure 3Figure 3

Bottom Line: We have shown previously that the proapoptotic effects of butyrate on AA/C1 human adenoma cells were reduced in the presence of bile acids.Butyrate-induced apoptosis was reduced by inhibitors of PKC-delta (Rottlerin), p38 MAP kinase (SB202190) and caspase 3 (DEVD-fmk), whereas the proliferative/survival effects of UDCA were blocked by inhibitors of PKC-alpha (Gö6976) and MEK 1 (PD98059).The effects of butyrate and bile acids are therefore mediated by the differential activation of signalling pathways that are known to regulate apoptosis.

View Article: PubMed Central - PubMed

Affiliation: Department of Immunology, The Medical School, Birmingham University, UK.

ABSTRACT
Butyrate, produced in the colon by fermentation of dietary fibre, induces apoptosis in colon adenoma and cancer cell lines, which may contribute to protection against colorectal cancer. However, butyrate is present in the colon along with other dietary factors, including unconjugated bile acids, which are tumour promoters. We have shown previously that the proapoptotic effects of butyrate on AA/C1 human adenoma cells were reduced in the presence of bile acids. To determine the cellular basis of this interaction, we examined the effects of butyrate and the secondary bile acid ursodeoxycholic acid (UDCA) on signalling pathways known to regulate apoptosis using AA/C1 cells. Butyrate activated PKC-delta and p38 MAP (mitogen-activated protein) kinase, whereas UDCA activated PKC-alpha and p42/44 MAP kinase. Butyrate treatment also resulted in the caspase-3-mediated proteolysis of PKC-delta. Butyrate-induced apoptosis was reduced by inhibitors of PKC-delta (Rottlerin), p38 MAP kinase (SB202190) and caspase 3 (DEVD-fmk), whereas the proliferative/survival effects of UDCA were blocked by inhibitors of PKC-alpha (Gö6976) and MEK 1 (PD98059). The effects of butyrate and bile acids are therefore mediated by the differential activation of signalling pathways that are known to regulate apoptosis.

Show MeSH
Related in: MedlinePlus