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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 treatment on PKC isoenzyme activation. PKC isoenzymes (α, βl, βll and δ) were measured by Western blotting in soluble and particulate fractions of (A) AA/C1 cells treated with or without 6 mM sodium butyrate for 2 h or (C) 10 μM UDCA for 24 h. (B) The 40 kDa fragment of PKC-δ was detected in whole cell lysates of AA/C1 cells treated for 18 h with 6 mM sodium butyrate in the absence or presence of the caspase 3 inhibitor Ac-DEVD-fmk. β-Actin was also measured as a loading control. The estimated molecular weights on the immunoreactive bands in (A) are shown on the right side of the figure. The blots shown are representative of three separate experiments performed.
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fig2: Effect of butyrate and UDCA treatment on PKC isoenzyme activation. PKC isoenzymes (α, βl, βll and δ) were measured by Western blotting in soluble and particulate fractions of (A) AA/C1 cells treated with or without 6 mM sodium butyrate for 2 h or (C) 10 μM UDCA for 24 h. (B) The 40 kDa fragment of PKC-δ was detected in whole cell lysates of AA/C1 cells treated for 18 h with 6 mM sodium butyrate in the absence or presence of the caspase 3 inhibitor Ac-DEVD-fmk. β-Actin was also measured as a loading control. The estimated molecular weights on the immunoreactive bands in (A) are shown on the right side of the figure. The blots shown are representative of three separate experiments performed.

Mentions: PKC-α, βl, βll and δ were detected in AA/C1 cells and were the predominant isoenzymes expressed in these cells (Figure 2AFigure 2


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 treatment on PKC isoenzyme activation. PKC isoenzymes (α, βl, βll and δ) were measured by Western blotting in soluble and particulate fractions of (A) AA/C1 cells treated with or without 6 mM sodium butyrate for 2 h or (C) 10 μM UDCA for 24 h. (B) The 40 kDa fragment of PKC-δ was detected in whole cell lysates of AA/C1 cells treated for 18 h with 6 mM sodium butyrate in the absence or presence of the caspase 3 inhibitor Ac-DEVD-fmk. β-Actin was also measured as a loading control. The estimated molecular weights on the immunoreactive bands in (A) are shown on the right side of the figure. The blots shown are representative of three separate experiments performed.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC2376332&req=5

fig2: Effect of butyrate and UDCA treatment on PKC isoenzyme activation. PKC isoenzymes (α, βl, βll and δ) were measured by Western blotting in soluble and particulate fractions of (A) AA/C1 cells treated with or without 6 mM sodium butyrate for 2 h or (C) 10 μM UDCA for 24 h. (B) The 40 kDa fragment of PKC-δ was detected in whole cell lysates of AA/C1 cells treated for 18 h with 6 mM sodium butyrate in the absence or presence of the caspase 3 inhibitor Ac-DEVD-fmk. β-Actin was also measured as a loading control. The estimated molecular weights on the immunoreactive bands in (A) are shown on the right side of the figure. The blots shown are representative of three separate experiments performed.
Mentions: PKC-α, βl, βll and δ were detected in AA/C1 cells and were the predominant isoenzymes expressed in these cells (Figure 2AFigure 2

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