Apoptosis in colorectal tumour cells: Induction by the short chain fatty acids butyrate, propionate and acetate and by the bile salt deoxycholate

Hague, Angela; Elder, Douglas J. E.; Hicks, Daniel; Paraskeva, Christos

doi:10.1002/ijc.2910600322

Cited by 388 publications

(279 citation statements)

References 27 publications

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“…In our in vitro cell culture system, cells which spontaneously detach from the tissue culture flask during routine cell culture and float in the medium have previously been shown to be apoptotic (Hague et al, 1993a;Bracey et al, 1995). This apoptotic population has previously been demonstrated to increase in the adenoma-derived cell lines PC/AA/C1 and S/RG/C2 and PC/AA/ C1/SB10 following treatment with sodium butyrate, but not with TGFb 1 (Hague et al, 1993a(Hague et al, , 1995. To determine whether spontaneous and butyrate-induced floating, apoptotic cells were the end point of a differentiation pathway (i.e.…”

Section: Both Spontaneously-derived and Butyrate-induced Apoptosis Ocmentioning

confidence: 98%

Butyrate- but not TGFβ1-induced apoptosis of colorectal adenoma cells is associated with increased expression of the differentiation markers E-cadherin and alkaline phosphatase

1997

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Sodium butyrate and transforming growth factor b (TGFb 1 ) are growth inhibitory to colonic adenoma cell lines. Butyrate induces apoptosis, whereas in some adenoma cell lines, TGFb 1 can be growth inhibitory without apoptosis. In this report, we show that the adenoma cell line PC/BH/C1 undergoes apoptosis in response to TGFb 1 . Butyrate induced cell death is preceded by the induction of two markers of colonic differentiation ± alkaline phosphatase (ALP) activity and E-cadherin protein expression. However, TGFb 1 -induced apoptosis was not accompanied by induction of these differentiation markers. It is possible that the apoptosis induced by TGFb 1 in the adenoma cell line PC/BH/C1 is due to conflicting signals, as downregulation of c-myc protein in response to TGFb 1 occurs only slowly in this cell line. Development of resistance to TGFb 1 in colonic tumours may involve two separate stages ± resistance to growth inhibition and resistance to TGFb 1 -induced apoptosis. Our results indicate that sodium butyrate induces apoptosis via differentiation, but TGFb 1 induces apoptosis by a differentiationindependent mechanism. As for butyrate, the induction of Ecadherin expression is a potentially important chemopreventative action, since increased E-cadherin expression has been correlated with decreased metastatic potential. This is the first report of induction of E-cadherin by a naturally occurring factor in the diet. Butyrate may reduce tumour growth and invasion, not only as a result of the induction of apoptosis, but also through increased expression of E-cadherin.

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Section: Both Spontaneously-derived and Butyrate-induced Apoptosis Ocmentioning

confidence: 98%

Butyrate- but not TGFβ1-induced apoptosis of colorectal adenoma cells is associated with increased expression of the differentiation markers E-cadherin and alkaline phosphatase

1997

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“…SCFAs possess antitumor activities by inducing caspase-3-mediated apoptosis. 11 To determine the interconnection between propionate-induced autophagy and apoptosis, autophagy inhibitors were applied to examine the cell viability of HCT116 and SW480 cells during propionate treatment. The punctate GFP-LC3 formation observed in the cells treated with propionate was significantly reduced in cells pretreated with 3-MA at 2 mM (Figure 7a and b).…”

Section: Mitotracker®mentioning

confidence: 99%

“…11 Interestingly, SCFAs have been reported to increase the expression of a broad range of mitochondria-related genes and a spectrum of genes related to protein turnover, but the physiological relevance is yet to be understood. 12 Herein we report that SCFAs, particularly propionate, induced autophagy and induction of autophagy attenuated the therapeutic efficacy of SCFAs toward colon cancer.…”

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confidence: 99%

Short-chain fatty acids induced autophagy serves as an adaptive strategy for retarding mitochondria-mediated apoptotic cell death

et al. 2010

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Short-chain fatty acids (SCFAs) are the major by-products of bacterial fermentation of undigested dietary fibers in the large intestine. SCFAs, mostly propionate and butyrate, inhibit proliferation and induce apoptosis in colon cancer cells, but clinical trials had mixed results regarding the anti-tumor activities of SCFAs. Herein we demonstrate that propionate and butyrate induced autophagy in human colon cancer cells to dampen apoptosis whereas inhibition of autophagy potentiated SCFA induced apoptosis. Colon cancer cells, after propionate treatment, exhibited extensive characteristics of autophagic proteolysis: increased LC3-I to LC3-II conversion, acidic vesicular organelle development, and reduced p62/SQSTM1 expression. Propionateinduced autophagy was associated with decreased mTOR activity and enhanced AMP kinase activity. The elevated AMPKa phosphorylation was associated with cellular ATP depletion and overproduction of reactive oxygen species due to mitochondrial dysfunction involving the induction of MPT and loss of Dw. In this context, mitochondria biogenesis was initiated to recover cellular energy homeostasis. Importantly, when autophagy was prevented either pharmacologically (3-MA or chloroquine) or genetically (knockdown of ATG5 or ATG7), the colon cancer cells became sensitized toward propionate-induced apoptosis through activation of caspase-7 and caspase-3. The observations indicate that propionate-triggered autophagy serves as an adaptive strategy for retarding mitochondria-mediated apoptotic cell death, whereas application of an autophagy inhibitor (Chloroquine) is expected to enhance the therapeutic efficacy of SCFAs in inducing colon tumor cell apoptosis.

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“…It is the preferred metabolic fuel of the healthy colonic epithelium, providing over 60% of the colonocytes' energy requirements (Cummings, 1984). In addition, it induces growth inhibition and terminal differentiation in a variety of human colon cancer cell lines (Kruh, 1982;Hague et al, 1995). These effects are correlated with changes in the expression of various genes associated with these processes (Archer et al, 1998;Siavoshian et al, 2000;Hague et al, 1997).…”

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confidence: 99%

Molecular changes in the expression of human colonic nutrient transporters during the transition from normality to malignancy

et al. 2002

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Healthy colonocytes derive 60 -70% of their energy supply from short-chain fatty acids, particularly butyrate. Butyrate has profound effects on differentiation, proliferation and apoptosis of colonic epithelial cells by regulating expression of various genes associated with these processes. We have previously shown that butyrate is transported across the luminal membrane of the colonic epithelium via a monocarboxylate transporter, MCT1. In this paper, using immunohistochemistry and in situ hybridisation histochemistry, we have determined the profile of MCT1 protein and mRNA expression along the crypt to surface axis of healthy human colonic tissue. There is a gradient of MCT1 protein expression in the apical membrane of the cells along the crypt-surface axis rising to a peak in the surface epithelial cells. MCT1 mRNA is expressed along the cryptsurface axis and is most abundant in cells lining the crypt. Analysis of healthy colonic tissues and carcinomas using immunohistochemistry and Western blotting revealed a significant decline in the expression of MCT1 protein during transition from normality to malignancy. This was reflected in a corresponding reduction in MCT1 mRNA expression, as measured by Northern analysis. Carcinoma samples displaying reduced levels of MCT1 were found to express the high affinity glucose transporter, GLUT1, suggesting that there is a switch from butyrate to glucose as an energy source in colonic epithelia during transition to malignancy. The expression levels of MCT1 in association with GLUT1 could potentially be used as determinants of the malignant state of colonic tissue.

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Apoptosis in colorectal tumour cells: Induction by the short chain fatty acids butyrate, propionate and acetate and by the bile salt deoxycholate

Cited by 388 publications

References 27 publications

Butyrate- but not TGFβ1-induced apoptosis of colorectal adenoma cells is associated with increased expression of the differentiation markers E-cadherin and alkaline phosphatase

Butyrate- but not TGFβ1-induced apoptosis of colorectal adenoma cells is associated with increased expression of the differentiation markers E-cadherin and alkaline phosphatase

Short-chain fatty acids induced autophagy serves as an adaptive strategy for retarding mitochondria-mediated apoptotic cell death

Molecular changes in the expression of human colonic nutrient transporters during the transition from normality to malignancy

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