PPARγ is a key target of butyrate-induced caspase-3 activation in the colorectal cancer cell line Caco-2

Schwab, Markus; Reynders, Veerle; Ulrich, S.; Zahn, Nadine; Stein, Jürgen M.; Schröder, Oliver

doi:10.1007/s10495-006-9788-2

Cited by 53 publications

(32 citation statements)

References 52 publications

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“…It is tempting to propose that RS-75 and inulin supplementation modulated the Treg compartment by causing changes in the gut's microbial ecology, resulting in increased butyrate levels that subsequently activate PPAR g (41). Although there was no direct correlation between improved lesions due to dietary fiber and inflammatory markers, clinically effective fibers induced immunoregulation, as exemplified by upregulated SOCS3 by SCF, upregulated PPARg by SCF and RS-75, increased Treg by RS-75 and inulin, and suppressed PP-derived IFNg by SCF, RS-75, and inulin.…”

Section: Discussionmentioning

confidence: 99%

Soluble Fibers and Resistant Starch Ameliorate Disease Activity in Interleukin-10–Deficient Mice with Inflammatory Bowel Disease

Bassaganya‐Riera

DiGuardo²,

Viladomiu

et al. 2011

The Journal of Nutrition

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Our goal in this study was to determine the potential for dietary fibers to prevent gut inflammation in IL-10-deficient (IL-10(-/-)) mice. C57BL/6J wild-type (WT) mice (n = 90) and IL-10(-/-) mice (n = 185) were assigned to a control diet or diets supplemented with PROMITOR soluble corn fiber (SCF), STA-LITE III polydextrose (PDX), Biogum (BG), Pullulan (PI-20), PROMITOR resistant starch-75 (RS-75), SCF&BG, RS-75&BG, and inulin (4 g fiber/100 g diet). On d 47, spleen, mesenteric lymph nodes (MLN), duodenum, jejunum, ileum, and colon were macroscopically and histologically evaluated. The spleen and Peyer's patches (PP) were collected for isolating mononuclear cells and measuring the percentages of regulatory T cells (Treg) and cytokines produced by CD4(+) T cells (i.e. IFNγ and IL-10). Dietary supplementation with RS-75, SCF, RS-75&BG, and inulin ameliorated disease activity on d 47. Dietary RS-75 and inulin supplementation decreased ileal and colonic inflammatory lesions. RS-75, SCF, and inulin decreased IFNγ production by effector CD4(+) T cells from PP and RS-75 increased the IL-10-expressing cells in spleen of WT mice. Dietary SCF, PDX, BG, PI-20, and RS-75 upregulated colonic PPARγ expression in WT mice and SCF upregulated Supressor of cytokine signaling 3 in IL-10(-/-) mice. These data suggest that soluble fibers and resistant starch influence Treg cells, IFNγ, and colonic PPARγ expression to suppress gut inflammation.

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Section: Discussionmentioning

confidence: 99%

Soluble Fibers and Resistant Starch Ameliorate Disease Activity in Interleukin-10–Deficient Mice with Inflammatory Bowel Disease

Bassaganya‐Riera

DiGuardo²,

Viladomiu

et al. 2011

The Journal of Nutrition

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“…Butyrate has the capacity to modulate histone acetylation by acting as a potent inhibitor of histone deacetylases (HDACs) and thereby modifies transcriptional activity of several genes. Described effects of butyrate include the downregulation of cyclin D1 (CCND1) [Lallemand et al, 1996], the induction of the inhibitor of cyclin-dependant kinases p21 WAF1/Cip1 (CDKN1A) [Nakano et al, 1997] and the peroxisome proliferator activated receptor gamma (PPARg) [Schwab et al, 2006] finally leading to the blockage of the cell cycle and the induction of apoptosis in colon cancer cells. The mediators of this effect are still poorly characterized, but in recent years, several genes have been identified, which are regulated in a butyrate-dependent manner.…”

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A bipartite butyrate‐responsive element in the human calretinin (CALB2) promoter acts as a repressor in colon carcinoma cells but not in mesothelioma cells

Häner

Henzi

Pfefferli

et al. 2009

J of Cellular Biochemistry

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The short-chain fatty acid butyrate plays an essential role in colonic mucosa homeostasis through the capacity to block the cell cycle, regulate differentiation and to induce apoptosis. The beneficial effect of dietary fibers on preventing colon cancer is essentially mediated through butyrate, derived from luminal fermentation of fibers by intestinal bacteria. In epithelial cells of the colon, both in normal and colon cancer cells, the expression of several genes is positively or negatively regulated by butyrate likely through modulation of histone acetylation and thereby affecting the transcriptional activity of genes. Calretinin (CALB2) is a member of the EF-hand family of Ca 2þ -binding proteins and is expressed in a majority of poorly differentiated colon carcinoma and additionally in mesothelioma of the epithelioid and mixed type. Since CALB2 is one of the genes negatively regulated by butyrate in colon cancer cells and butyrate decreases calretinin protein expression levels in those cells, we investigated whether expression is regulated via putative butyrate-responsive elements (BRE) in the human CALB2 promoter. We identified two elements that act as butyrate-sensitive repressors in all colon cancer cell lines tested (CaCo-2, HT-29, Co-115/3). In contrast, in cells of mesothelial origin, MeT-5A and ZL34, the same two elements do not operate as butyrate-sensitive repressors and calretinin expression levels are insensitive to butyrate indicative of cell type-specific regulation of the CALB2 promoter. Calretinin expression in colon cancer cells is negatively regulated by butyrate via a bipartite BRE flanking the TATA box and this may be linked to butyrate's chemopreventive activity.

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“…7 It has recently been shown that 1 mM NaB is the best working concentration to activate the differentiation program in CRCs without triggering apoptosis, whereas 5 mM NaB is sufficient to induce a p53-independent apoptotic cell death by activating a pathway involving p38, PPARg and caspases. 6,8 Several intracellular signaling cascades have been implicated in the regulation of the proliferation-differentiation balance in enterocytes by the coordinated expression of the genome in response to environmental cues. During enterocyte differentiation of CRCs the ERK pathway is switched off, whereas PI 3 K class I and p38 activities are increased and essential for full differentiation.…”

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A novel cell type-specific role of p38α in the control of autophagy and cell death in colorectal cancer cells

et al. 2006

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Cancer develops when molecular pathways that control the fine balance between proliferation, differentiation, autophagy and cell death undergo genetic deregulation. The prospects for further substantial advances in the management of colorectal cancer reside in a systematic genetic and functional dissection of these pathways in tumor cells. In an effort to evaluate the impact of p38 signaling on colorectal cancer cell fate, we treated HT29, Caco2, Hct116, LS174T and SW480 cell lines with the inhibitor SB202190 specific for p38a/b kinases. We report that p38a is required for colorectal cancer cell homeostasis as the inhibition of its kinase function by pharmacological blockade or genetic inactivation causes cell cycle arrest, autophagy and cell death in a cell type-specific manner. Deficiency of p38a activity induces a tissue-restricted upregulation of the GABARAP gene, an essential component of autophagic vacuoles and autophagosomes, whereas simultaneous inhibition of autophagy significantly increases cell death by triggering apoptosis. These data identify p38a as a central mediator of colorectal cancer cell homeostasis and establish a rationale for the evaluation of the pharmacological manipulation of the p38a pathway in the treatment of colorectal cancer. Colorectal cancer is a major health concern, with more than 1 000 000 new cases and 500 000 deaths expected worldwide per year.1 Prognostic evaluation is currently based on histological appearance, and there are no molecular markers internationally recognized as standard predictor factors. The conventional therapy involving surgery and adjuvant therapy seems to give rise to improvements in progression-free and overall survival. Nevertheless about 50% of patients die within 5 years owing to metastasis or recurrent disease.2 The prospects for further substantial advances in the management of colorectal cancer reside in a systematic genetic and functional dissection of cell cycle and cell death regulatory pathways in tumor cells in order to identify differential cellular effects of agents that may have a direct impact on cancer therapy.During the last decade, a number of deacetylase inhibitors (DI) have been identified. These DI induce tumor cells to undergo growth arrest, differentiation, and/or apoptosis in culture and in animal models, at doses that seem to be nontoxic and appear to be selective. Butyrate, a DI that is naturally formed in the human colon, is able to reduce the size and the number of tumors in rat models of bowel cancer.3 In vitro, sodium butyrate (NaB) is a potent differentiating agent for several colorectal cancer cell lines (CRCs).4-6 NaB-mediated cell cycle withdrawal of CRCs appears to be dependent on acetylation of histones and consequent changes in transcription, requiring continuous protein synthesis and the expression of p21. 7 It has recently been shown that 1 mM NaB is the best working concentration to activate the differentiation program in CRCs without triggering apoptosis, whereas 5 mM NaB is sufficient to induce a p53-independent...

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PPARγ is a key target of butyrate-induced caspase-3 activation in the colorectal cancer cell line Caco-2

Abstract: Our data clearly unveil PPARgamma as a key target in the butyrate-induced signalling cascade leading to apoptosis via caspase-3 in Caco-2 cells.

Cited by 53 publications

References 52 publications

Soluble Fibers and Resistant Starch Ameliorate Disease Activity in Interleukin-10–Deficient Mice with Inflammatory Bowel Disease

Soluble Fibers and Resistant Starch Ameliorate Disease Activity in Interleukin-10–Deficient Mice with Inflammatory Bowel Disease

A bipartite butyrate‐responsive element in the human calretinin (CALB2) promoter acts as a repressor in colon carcinoma cells but not in mesothelioma cells

A novel cell type-specific role of p38α in the control of autophagy and cell death in colorectal cancer cells

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