Ursodeoxycholic acid differentially affects three types of sphingomyelinase in human colon cancer Caco 2 cells

Liu, Fuli; Cheng, Yajun; Wu, Jun; Tauschel, Horst-Dietmar; Duan, Rui‐Dong

doi:10.1016/j.canlet.2005.04.016

Cited by 27 publications

(19 citation statements)

References 22 publications

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“…It is well-known that PSC increases the risk of hepatobiliary cancer (Yang et al, 2001;Ohata et al, 2003;Lazaridis and Gores, 2006) as well as colon cancer associated with colitis (Broome and Bergquist, 2006). The disease is treated with ursodeoxycholic acid to decrease the risk of colorectal cancer (Pardi et al, 2003) and ursodeoxycholic acid has been shown to induce expression alk-SMase in both animal models and cell culture studies (Cheng et al, 1999;Liu et al, 2006). We therefore raised a question whether this ectoenzyme may also be an antitumour factor both in development of primary hepatic and biliary carcinomas and in the regulation of metastatic tumour growth.…”

Section: Discussionmentioning

confidence: 99%

“…Determination of SMase, galactosidase and proteins The activities of acid, neutral and alk-SMase were determined as described, using choline-labelled SM ([ 14 C-SM]) as substrate in different assay buffers (Duan and Nilsson, 2000;Liu et al, 2006). The activity of b-galactosidase in COS-7 cells after transfection was assayed by a b-gal assay kit (Invitrogen), using ortho-nitrophenyl-b-galactopyranoside as substrate (Wu et al, 2004a).…”

Section: Methodsmentioning

confidence: 99%

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Identification of aberrant forms of alkaline sphingomyelinase (NPP7) associated with human liver tumorigenesis

Cheng

Wu²,

Hertervig

et al. 2007

Br J Cancer

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Alkaline sphingomyelinase (alk-SMase) is expressed in the intestine and human liver. It may inhibit colonic tumorigenesis, and loss of function mutations have been identified in human colon cancer. The present study investigates its expression in human liver cancer. In HepG2 liver cancer cells, RT -PCR identified three transcripts with 1.4, 1.2 and 0.4 kb, respectively. The 1.4 kb form is the wild-type cDNA with five translated exons, the 1.2 kb product lacks exon 4 and the 0.4 kb form is a combination of exons 1 and 5. Genomic sequence showed that these aberrant transcripts were products of alternative splicing. Transient expression of the 1.2 kb form showed no alk-SMase activity. In HepG2 cells, the alk-SMase activity is low in monolayer condition and increased with cell polarisation. Coexistence of 1.4 and 1.2 kb forms was also identified in one hepatoma biopsy. GenBank search identified a cDNA clone from human liver tumour, which codes a protein containing full length of alk-SMase plus a 73-amino-acid tag at the N terminus. The aberrant form was translated by an alternative starting codon upstream of the wild-type mRNA. Expression study showed that linking the tag markedly reduced the enzyme activity. We also analysed human liver biopsy samples and found relatively low alkSMase activity in diseases with increased risk of liver tumorigenesis. In conclusion, expression of alk-SMase is changed in hepatic tumorigenesis, resulting in loss or marked reduction of the enzyme function.

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Section: Discussionmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Identification of aberrant forms of alkaline sphingomyelinase (NPP7) associated with human liver tumorigenesis

Cheng

Wu²,

Hertervig

et al. 2007

Br J Cancer

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“…Ceramide can be generated either by de novo synthesis via activation of ceramide synthase or by sphingomyelin hydrolysis, following activation of acid, neutral or alkaline sphingomyelinases [6,7]. Although recent studies also involve neutral or alkaline sphingomyelinase in the induction of apoptosis [8,9], most studies investigated the role of acid sphingomyelinase-released ceramide in cell death. Ceramide has been shown to play a significant role in signalling triggered by both intrinsic and extrinsic apoptosis-inducing stimuli, which suggests that the mechanisms of ceramide-mediated cell death are complex and diverse.…”

Section: Introductionmentioning

confidence: 99%

Lysosomal ceramide mediates gemcitabine-induced death of glioma cells

et al. 2009

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“…Third, the expression of Alk-SMase can be induced by ursodeoxycholic acid both in rats [16] and in a human colon cancer derived cell line [17]. The effect is more potent on differentiated enterocytes than on proliferating cells.…”

Section: Introductionmentioning

confidence: 99%

Effects of bile diversion in rats on intestinal sphingomyelinases and ceramidase

Duan

Verkade

Cheng

et al. 2007

Biochimica et Biophysica Acta (BBA) - Molecular and Cell Biolog

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1 Summary:Alkaline sphingomyelinase (Alk-SMase) and neutral ceramidase (N-CDase) in the intestinal microvillar membrane are responsible for dietary sphingomyelin digestion. The activities of the enzymes require the presence of bile salt, and the enzymes can be released into the gut lumen in active forms by bile salts and trypsin. It is unclear to what extent that the intestinal presence of bile salts is critical for the intraluminal activity of these enzymes. We compared the activities of Alk-SMase, N-CDase, and other types of SMases in control and permanently bile diverted rats. In the intestinal tract of control rats, the activity of Alk-SMase was profoundly higher than those of acid and neutral SMases. Bile diversion reduced Alk-SMase activity by 85% in the small intestinal content, and by 68% in the faeces, but did not significantly change the activity in the intestinal mucosa. Western blot showed a marked reduction of the enzyme in the intestinal lumen but not mucosa. N-CDase activities both in the intestinal mucosa and content were reduced by bile diversion. Bile diversion also decreased aminopeptidase N activity in the content and increased that in the mucosa, but had no effects on that of alkaline phosphatase. In conclusion, the presence of bile salts is important for maintaining high intraluminal levels of Alk-SMase and N-CDase, two key enzymes for hydrolysis of sphingomyelin in the gut. We speculate that the sphingomyelin hydrolysis in cholestatic conditions is impaired not only by reduced hydrolytic activity but also by deficient dissociation of the enzymes from the membrane.

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Ursodeoxycholic acid differentially affects three types of sphingomyelinase in human colon cancer Caco 2 cells

Cited by 27 publications

References 22 publications

Identification of aberrant forms of alkaline sphingomyelinase (NPP7) associated with human liver tumorigenesis

Identification of aberrant forms of alkaline sphingomyelinase (NPP7) associated with human liver tumorigenesis

Lysosomal ceramide mediates gemcitabine-induced death of glioma cells

Effects of bile diversion in rats on intestinal sphingomyelinases and ceramidase

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