Butyrate-Induced Differentiation of Colon Cancer Cells Is PKC and JNK Dependent

Orchel, Arkadiusz; Dzierżewicz, Zofia; Parfiniewicz, Beata; Węglarz, Ludmiła; Wilczok, Tadeusz

doi:10.1007/s10620-005-2463-6

Cited by 80 publications

(75 citation statements)

References 52 publications

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“…Overexpression of PKCßII in colonic epithelium seems to results in hyperproliferation and an increased susceptibility to carcinogenesis with an early increase in carcinogenesis, whereas PKC was downregulated in colonic tumors (43,44). Data from Orchel et al (45) have shown that differentiation of Caco-2 cells by butyrate treatment is dependent on PKC and c-Jun N-terminal kinase (JNK) activity. In LIM1215 and CaCo-2 colon carcinoma cells, butyrate reduced total protein kinase C (PKC) activity and specifically reduced the expression of PKC· and PKCε subtypes, an effect that was reproduced by incubations with a specific inhibitor of histone deacetylase (46).…”

Section: Discussionmentioning

confidence: 99%

Butyrate-induced alterations of phosphoinositide metabolism, protein kinase C activity and reduced CD44 variant expression in HT-29 colon cancer cells

Kopp¹,

Fichter²,

Assert³

et al. 2009

Int J Mol Med

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Abstract. Initiation of cell growth and neoplastic transformation frequently involves activation of growth factor receptor-coupled tyrosine kinases and stimulation of the phosphoinositide second messenger system. Altered expression of CD44 variants was reported in several malignant tumor types with possible implications for tumor progression and prognosis. CD44 variant expression was reported to be associated with second messenger activation and differentiation. We therefore investigated the effects of butyrateinduced short-term differentiation on phosphoinositide signaling, phospholipase C and protein kinase C activity and alteration of CD44 variant expression in human HT-29 colon carcinoma cells. HT-29 cells were cultured with sodium butyrate for 6 days. Phosphoinositide turnover was measured by [32 P]orthophosphate incorporation and phospholipase C activity by determination of the release of [ 3 H]inositolphosphates from [ 3 H]myoinositol prelabeled cells. Protein kinase C activity was determined by histone III-S phosphorylation, PKC subtype expression by RNase protection analysis, and CD44 variant expression was determined by RT-PCR using variant-specific primers. Treatment of HT-29 human colon carcinoma cells with sodium butyrate caused a dose-dependent inhibition of cell proliferation (IC 50 , 2.5 mM) with morphologic signs of an enterocytic differentiation following 6 days of treatment. The phosphoinositide turnover as determined by 32 P-incorporation under non-equilibrium conditions showed a 30-40% inhibition of labeled phosphoinositides and phosphatidic acid and a dose-dependent inhibition of cholinergically stimulated phospholipase C activity as a secondary event following butyrate-induced enterocytic differentiation. However, long-term incubation of HT-29 cells with phorbol ester or an inhibitor of classical and novel PKC subtypes did not affect cell proliferation. In butyrate-treated HT-29 cells activation of calcium-dependent protein kinase C by cholinergic stimulation or phorbolester treatment induced an increase in membrane-bound cPKC activity, while expression of distinct high-molecular CD44 variant transcripts v3 (670 bp), v5 (940 bp) and v8 (535 bp) were drastically reduced after butyrate pretreatment. Enterocytic differentiation of HT-29 colon carcinoma cells seems to be associated with alterations in phosphoinositide resynthesis, phospholipase C activity and ligand/receptorinduced PKC translocation. The observed reduction of distinct high-molecular CD44v3, v5 and v8 variants following butyrate-induced differentiation indicates an association of specific CD44 variant expression with the malignant phenotype of HT-29 colon cancer cells, thus being possible targets for new diagnostic and therapeutic strategies.

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Section: Discussionmentioning

confidence: 99%

Butyrate-induced alterations of phosphoinositide metabolism, protein kinase C activity and reduced CD44 variant expression in HT-29 colon cancer cells

Kopp¹,

Fichter²,

Assert³

et al. 2009

Int J Mol Med

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“…2). Multiple intracellular kinases in the oncogenic or survival signaling pathways have been illustrated to be key players in butyrate actions (27,28). Western blotting using monoclonal antibody against the C terminus of AKAP12 showed decreased expression of the full-length protein and an appearance of a truncated isoform at a molecular mass…”

Section: Cluster A: Growth Arrestmentioning

confidence: 99%

Quantitative and Temporal Proteome Analysis of Butyrate-treated Colorectal Cancer Cells

Tan¹,

Tan

Lin

et al. 2008

Molecular & Cellular Proteomics

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Colorectal cancer is one of the most common cancers in developed countries, and its incidence is negatively associated with high dietary fiber intake. Butyrate, a shortchain fatty acid fermentation by-product of fiber induces cell maturation with the promotion of growth arrest, differentiation, and/or apoptosis of cancer cells. The stimulation of cell maturation by butyrate in colonic cancer cells follows a temporal progression from the early phase of growth arrest to the activation of apoptotic cascades. Previously we performed two-dimensional DIGE to identify differentially expressed proteins induced by 24-h butyrate treatment of HCT-116 colorectal cancer cells. Herein we used quantitative proteomics approaches using iTRAQ (isobaric tags for relative and absolute quantitation), a stable isotope labeling methodology that enables multiplexing of four samples, for a temporal study of HCT-116 cells treated with butyrate. In addition, cleavable ICAT, which selectively tags cysteine-containing proteins, was also used, and the results complemented those obtained from the iTRAQ strategy. Selected protein targets were validated by real time PCR and Western blotting. A model is proposed to illustrate our findings from this temporal analysis of the butyrateresponsive proteome that uncovered several integrated cellular processes and pathways involved in growth arrest, apoptosis, and metastasis. These signature clusters of butyrate-regulated pathways are potential targets for novel chemopreventive and therapeutic drugs for treatment of colorectal cancer. Molecular & Cellular Proteomics 7:1174 -1185, 2008.In developed countries, colorectal cancer is a prevalent disease with high mortality and morbidity rates (1). This disease has emerged as the top malignancy in Singapore. Environmental factors are responsible for about 80% of the cases, whereas genetic predisposition accounts for the minority 20% of cases. Epidemiological evidence suggests that high intake of dietary fiber reduces the incidence and risk of this neoplasm (2, 3). A wealth of studies has shown that butyrate produced from anaerobic fermentation of indigestible carbohydrate is the molecule responsible for the chemopreventive properties of a fiber-rich diet (4 -6).Although butyrate serves as an energy source for normal colonocytes, in vivo and in vitro studies have shown that at physiological concentrations this natural short-chain fatty acid mediates cell maturation with the promotion of growth arrest followed by differentiation and/or apoptosis of cancer cells (7-11). These biological effects are crucial in colorectal cancer therapy as colonic transformation is characterized by multistage alterations of tissue homeostasis resulting in aberrant cell division and/or cell death (12, 13). Butyrate has been purported as a potential anticancer agent. This initiated notable research in identifying proteins that contribute to its biological effects (14, 15). However, most of these investigations focused on one target at any one time and were thus unable to systematica...

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“…3 In vitro, sodium butyrate (NaB) is a potent differentiating agent for several colorectal cancer cell lines (CRCs). [4][5][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 apoptotic cell death by activating a pathway involving p38, PPARg and caspases.…”

mentioning

confidence: 99%

“…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.…”

mentioning

confidence: 99%

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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Butyrate-Induced Differentiation of Colon Cancer Cells Is PKC and JNK Dependent

Cited by 80 publications

References 52 publications

Butyrate-induced alterations of phosphoinositide metabolism, protein kinase C activity and reduced CD44 variant expression in HT-29 colon cancer cells

Butyrate-induced alterations of phosphoinositide metabolism, protein kinase C activity and reduced CD44 variant expression in HT-29 colon cancer cells

Quantitative and Temporal Proteome Analysis of Butyrate-treated Colorectal Cancer 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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