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Michael Glei - One of the best experts on this subject based on the ideXlab platform.
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Impact of processing degree on fermentation profile and chemopreventive effects of oat and waxy barley in LT97 Colon Adenoma cells
European Food Research and Technology, 2020Co-Authors: Wiebke Schlormann, Stefan Lorkowski, F. Keller, S. Zetzmann, C. Dawczynski, Michael GleiAbstract:The chemopreventive effects of β-glucan-rich cereals such as oat and barley (beta®barley) have been examined previously, but studies comparing fermentation characteristics and chemopreventive effects of oat and barley of different processing stages are rare. Therefore, the present study aims at investigating the fermentation end points (pH values, concentrations of short-chain fatty acids (SCFA) and ammonia) in fermentation supernatants (FS) obtained from differently processed oat and barley samples (kernels, thick and thin flakes). Chemopreventive effects of FS, such as growth inhibition, apoptosis, and induction of cell cycle- and redox-relevant genes ( p21 , SOD2 ), were analysed in LT97 Colon Adenoma cells. After fermentation, pH values were reduced (∆ pH − 1.3, on average) and SCFA concentrations were increased (∆ + 59 mmol/L, on average) with a shift towards butyrate formation in FS obtained from oat and barley samples compared to the fermentation negative control (FS blank). Ammonia was reduced more effectively in FS obtained from barley (∆ − 4.6 mmol/L, on average) than from oat samples (∆ − 1.0 mmol/L, on average). Treatment of LT97 cells with FS resulted in a time- and dose-dependent reduction of cell number, an increase in caspase-3 activity (up to 9.0-fold after 24 h, on average) and an induction of p21 (2.1-fold, on average) and SOD2 (2.3-fold, on average) mRNA expression, while no genotoxic effects were observed. In general, the results indicate no concrete effect of the type of cereal or processing stage on fermentation and chemopreventive effects of oat and barley.
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chemopreventive potential of in vitro fermented raw and roasted hazelnuts in lt97 Colon Adenoma cells
Anticancer Research, 2018Co-Authors: Michael Glei, Sonja Fischer, Julia Lamberty, Diana Ludwig, Stefan Lorkowski, Wiebke SchlormannAbstract:BACKGROUND/AIM Due to their unique composition of health-promoting compounds, the consumption of hazelnuts may contribute to the prevention of Colon cancer. MATERIALS AND METHODS Since hazelnuts are often consumed roasted, the impact of different roasting conditions (RC1=140.6°C/25 min, RC2=155.1°C/20 min and RC3=180.4°C/21 min) on chemopreventive effects of in vitro fermented hazelnuts was analyzed in LT97 Colon Adenoma cells. RESULTS FS (2.5%) of raw and roasted hazelnuts reduced H2O2-induced DNA damage while 5% FS significantly induced gene expression of SOD2 (3.0-fold) and GSTP1 (2.1-fold). GPx1 mRNA levels were significantly decreased (0.6-fold) by FS (2.5%). The growth of LT97 cells was significantly reduced by hazelnut FS in a time- and dose-dependent manner. Hazelnut FS (5%) increased the numbers of early apoptotic cells (9.6% on average) and caspase-3 activities (6.4-fold on average). CONCLUSION These results indicate a chemopreventive potential of in vitro fermented hazelnuts which is largely unaffected by the roasting process.
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In vitro-fermented raw and roasted walnuts induce expression of CAT and GSTT2 genes, growth inhibition, and apoptosis in LT97 Colon Adenoma cells.
Nutrition research (New York N.Y.), 2017Co-Authors: Wiebke Schlormann, Diana Ludwig, Julia Lamberty, Stefan Lorkowski, Michael GleiAbstract:Walnuts are rich in bioactive compounds such as polyunsaturated fatty acids, polyphenols, and dietary fiber. Therefore, the consumption of walnuts can contribute to a healthy diet and may reduce the risk for Colon cancer. Heat treatment like roasting may change the chemical composition of walnuts and therefore their chemopreventive properties. Therefore, the hypothesis of the present study is that different roasting conditions (RCs) alter the chemopreventive effects of walnuts. Thus, the aim of the present study was to investigate whether different RCs (RC1=139.7°C/25 min, RC2=154.5°C/20 min, and RC3=185.5°C/25 min) alter the chemopreventive effects of walnuts. Raw and roasted walnuts were subjected to in vitro digestion and fermentation. After treatment of LT97 Colon Adenoma cells with fermentation supernatants (FSs), expression of CAT, SOD2, GPx1, GSTP1, and GSTT2 genes as well as cell growth and apoptosis was examined. In comparison to the fermentation blank control, walnut FS particularly increased mRNA levels of CAT 1.7-fold and GSTT2 3.1-fold, whereas GPx1 levels were significantly decreased 0.6-fold. Walnut FS decreased growth of Adenoma cells in a time- and dose-dependent manner. In particular, higher concentrations of walnut FS (5%) significantly increased the number of early apoptotic cells 2.0-fold and induced caspase-3 activity 6.8-fold compared with the blank control. The roasting process had no direct impact on the observed effects. In sum, our results indicate that walnuts exhibit chemopreventive effects regarding the risk for Colon cancer development by inducing expression of genes involved in detoxification (CAT, GSTT2) and by inducing growth inhibition and apoptosis in Colon Adenoma cells unaffected by moderate roasting.
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Influence of roasting on the chemopreventive potential of in vitro fermented almonds in LT97 Colon Adenoma cells.
International journal of food sciences and nutrition, 2017Co-Authors: Wiebke Schlormann, Sonja Fischer, Stefan Lorkowski, Christian Saupe, Tülin Dinc, Michael GleiAbstract:The consumption of almonds may contribute to the prevention of Colon cancer due to their unique composition of health promoting compounds. Since almonds are often consumed roasted, the impact of different roasting (R) conditions (R1 = 139.2 °C/25 min, R2 = 161.5 °C/20 min and R3 = 170.8 °C/15 min) on chemopreventive effects of in vitro-fermented almonds was analysed in LT97 Colon Adenoma cells. Fermentation supernatants (FS) of raw and roasted almonds had no genotoxic effects. FS obtained from raw or mildly roasted almonds (R1) significantly increased mRNA levels of CAT (4.6-fold), SOD2 (5.6-fold) and GSTP1 (3.9-fold) but not of GPx1. FS of almonds significantly reduced the growth of LT97 cells in a time- and dose-dependent manner. Treatment with 5% almonds FS increased the number of early apoptotic cells (17.4%, on average) and caspase-3 activity (4.9-fold, on average). The results indicate a chemopreventive potential of in vitro-fermented almonds which is largely independent of the roasting process.
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Chemopreventive potential of in vitro fermented nuts in LT97 Colon Adenoma and primary epithelial Colon cells.
Molecular carcinogenesis, 2017Co-Authors: Wiebke Schlormann, Julia Lamberty, Diana Ludwig, Stefan Lorkowski, Christian Saupe, Henning Mothes, Michael GleiAbstract:Due to their beneficial nutritional profile the consumption of nuts contributes to a healthy diet and might reduce Colon cancer risk. To get closer insights into potential mechanisms, the chemopreventive potential of different in vitro fermented nut varieties regarding the modulation of genes involved in detoxification (CAT, SOD2, GSTP1, GPx1) and cell cycle (p21, cyclin D2) as well as proliferation and apoptosis was examined in LT97 Colon Adenoma and primary epithelial Colon cells. Fermentation supernatants (FS) of nuts significantly induced mRNA expression of CAT (up to 4.0-fold), SOD2 (up to 2.5-fold), and GSTP1 (up to 2.3-fold), while GPx1 expression was significantly reduced by all nut FS (0.8 fold on average). Levels of p21 mRNA were significantly enhanced (up to 2.6-fold), whereas all nut FS significantly decreased cyclin D2 expression (0.4-fold on average). In primary epithelial cells, expression of CAT (up to 3.5-fold), GSTP1 (up to 3.0-fold), and GPx1 (up to 3.9-fold) was increased, whereas p21 and cyclin D2 levels were not influenced. Nut FS significantly inhibited growth of LT97 cells and increased levels of early apoptotic cells (8.4% on average) and caspase 3 activity (4.6-fold on average), whereas caspase 3 activity was not modulated in primary Colon cells. The differential modulation of genes involved in detoxification and cell cycle together with an inhibition of proliferation and induction of apoptosis in Adenoma cells might contribute to chemopreventive effects of nuts regarding Colon cancer.
Sanford D. Markowitz - One of the best experts on this subject based on the ideXlab platform.
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tissue specific patterns of gene expression in the epithelium and stroma of normal Colon in healthy individuals in an aspirin intervention trial
BMC Medical Genetics, 2015Co-Authors: Sushma S Thomas, Sanford D. Markowitz, Karen W Makar, Lin Li, Yingye Zheng, Peiying Yang, Lisa Levy, Rebecca Yvonne Rudolph, Paul D Lampe, Jeannette BiglerAbstract:Background Regular aspirin use reduces Colon Adenoma and carcinoma incidence. UDP-glucuronosyltransferases (UGT) are involved in aspirin metabolism and clearance, and variant alleles in UGT1A6 have been shown to alter salicylic acid metabolism and risk of Colon neoplasia.
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Tissue-specific patterns of gene expression in the epithelium and stroma of normal Colon in healthy individuals in an aspirin intervention trial
BMC Medical Genetics, 2015Co-Authors: Sushma S Thomas, Sanford D. Markowitz, Karen W Makar, Yingye Zheng, Peiying Yang, Lisa Levy, Rebecca Yvonne Rudolph, Paul D Lampe, Min Yan, Jeannette BiglerAbstract:Background Regular aspirin use reduces Colon Adenoma and carcinoma incidence. UDP-glucuronosyltransferases (UGT) are involved in aspirin metabolism and clearance, and variant alleles in UGT1A6 have been shown to alter salicylic acid metabolism and risk of Colon neoplasia. Methods In a randomized, cross-over, placebo-controlled trial of 44 healthy men and women, homozygous for UGT1A6*1 or UGT1A6*2, we explored differences between global epithelial and stromal expression, using Affymetrix U133 + 2.0 microarrays and tested effects of 60-day aspirin supplementation (325 mg/d) on epithelial and stromal gene expression and Colon prostaglandin E2 (PGE2) levels. Results No statistically significant differences in gene expression were observed in response to aspirin or UGT1A6 genotype, but tissue PGE2 levels were lower with aspirin compared to placebo (p
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Early loss of deleted in colorectal carcinoma gene transcript detected in a group of benign Colon Adenomas.
Journal of Biomedical Science, 2002Co-Authors: June L. Traicoff, James K V Willson, Sanford D. MarkowitzAbstract:We examined the expression of the putative tumor suppressor gene deleted in colorectal carcinoma (DCC) in human Colon Adenoma tissues and cell lines. One allele of DCC is deleted in 70% of human Colon carcinomas, and DCC expression is undetectable in 90% of Colon carcinoma cell lines. One DCC allele is also deleted in 50% of human Colon Adenomas, but results from protein expression studies have differed as to whether complete loss of DCC expression could occur in Colon Adenomas, or instead correlates with progression of Colon Adenoma to carcinoma. To further examine the timing of DCC expression loss in Colon Adenomas, we assayed DCC transcript levels in Adenoma cell lines and tissues. We measured DCC expression by a sensitive assay using Southern blot detection of the RT-PCR-amplified DCC transcript. DCC expression was negligible or greatly reduced in 4 of 14 Colon Adenomas, including 2 of 2 Adenoma cell lines and 2 of 12 Adenoma tissue samples. These data are the first evidence that expression of DCC transcript can be silenced in Colon Adenoma cell lines and tissues. These data indicate that loss of DCC expression occurs in some Colon Adenomas, but is insufficient to drive the Adenoma to carcinoma progression.
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Both Transforming Growth Factor-β and Substrate Release Are Inducers of Apoptosis in a Human Colon Adenoma Cell Line
Cancer research, 1995Co-Authors: Cheng Ya Wang, James K V Willson, James R. Eshleman, Sanford D. MarkowitzAbstract:Abstract VACO-330, a nontransformed cell line established from a human Colon Adenoma, undergoes spontaneous apoptosis and shedding of cells into the culture medium. Shed cells were shown to be apoptotic, both by nuclear morphology and by generation of a typical “laddered” pattern of degraded DNA. Quantitation of DNA released into the medium, compared with the amount retained on the plate, demonstrated that 6.2 ± 1.1% of the total cell mass underwent apoptotic death daily. The addition of transforming growth factor β (20 ng/ml) accelerated this spontaneous apoptotic rate 3.2-fold. Moreover, apoptosis could be rapidly induced in up to 45% of the VACO-330 cells by using brief exposure to a calcium chelating medium to release the cells from the substratum. We suggest that transforming growth factor β is a likely physiological regulator of apoptosis during maturation of the Colonic epithelial cells. We additionally suggest the existence of an alternate pathway, which at the time of shedding from the crypt induces apoptosis in Colonic epithelial cells that have escaped earlier apoptotic signals.
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A benign cultured Colon Adenoma bears three genetically altered Colon cancer oncogenes, but progresses to tumorigenicity and transforming growth factor-beta independence without inactivating the p53 tumor suppressor gene.
The Journal of clinical investigation, 1994Co-Authors: Sanford D. Markowitz, Lois Myeroff, Mark J. Cooper, June L. Traicoff, Mary Kochera, I James Lutterbaugh, Margaret Swiriduk, James K V WillsonAbstract:We describe the spontaneous progression of a Colon Adenoma cell line to tumorigenicity and growth factor independence. This system allows direct comparison of biologic stages of malignant progression with alterations of Colon cancer suppressor genes and oncogenes. VACO-235, a human Colon Adenoma cell line, is at early passages nontumorigenic in the nude mouse, unable to grow in soft agar, growth stimulated by serum and EGF, and growth inhibited by TGF-beta. VACO-235 daughter passages 93 and higher have in culture spontaneously progressed to being weakly tumorigenic, but retain all other growth characteristics of VACO-235 early passages. A mouse xenograft from late passage VACO-235 was reestablished in culture as the granddaughter cell line, VACO-411. VACO-411 is highly tumorigenic, clones in soft agar, and is unresponsive to serum, EGF, and TGF-beta. Early passage VACO-235 bears a mutant K-ras allele, bears only mutant APC alleles, expresses no DCC transcripts, and expresses only wild type p53 transcripts. VACO-411 retains the identical genotype, still expressing only wild type p53. Colonic cells after ras mutation, APC mutation, and DCC inactivation remain nontumorigenic and growth factor dependent. Malignant progression involves at least two additional steps, and in VACO-411 can proceed by a novel pathway not requiring p53 inactivation.
Wiebke Schlormann - One of the best experts on this subject based on the ideXlab platform.
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Impact of processing degree on fermentation profile and chemopreventive effects of oat and waxy barley in LT97 Colon Adenoma cells
European Food Research and Technology, 2020Co-Authors: Wiebke Schlormann, Stefan Lorkowski, F. Keller, S. Zetzmann, C. Dawczynski, Michael GleiAbstract:The chemopreventive effects of β-glucan-rich cereals such as oat and barley (beta®barley) have been examined previously, but studies comparing fermentation characteristics and chemopreventive effects of oat and barley of different processing stages are rare. Therefore, the present study aims at investigating the fermentation end points (pH values, concentrations of short-chain fatty acids (SCFA) and ammonia) in fermentation supernatants (FS) obtained from differently processed oat and barley samples (kernels, thick and thin flakes). Chemopreventive effects of FS, such as growth inhibition, apoptosis, and induction of cell cycle- and redox-relevant genes ( p21 , SOD2 ), were analysed in LT97 Colon Adenoma cells. After fermentation, pH values were reduced (∆ pH − 1.3, on average) and SCFA concentrations were increased (∆ + 59 mmol/L, on average) with a shift towards butyrate formation in FS obtained from oat and barley samples compared to the fermentation negative control (FS blank). Ammonia was reduced more effectively in FS obtained from barley (∆ − 4.6 mmol/L, on average) than from oat samples (∆ − 1.0 mmol/L, on average). Treatment of LT97 cells with FS resulted in a time- and dose-dependent reduction of cell number, an increase in caspase-3 activity (up to 9.0-fold after 24 h, on average) and an induction of p21 (2.1-fold, on average) and SOD2 (2.3-fold, on average) mRNA expression, while no genotoxic effects were observed. In general, the results indicate no concrete effect of the type of cereal or processing stage on fermentation and chemopreventive effects of oat and barley.
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chemopreventive potential of in vitro fermented raw and roasted hazelnuts in lt97 Colon Adenoma cells
Anticancer Research, 2018Co-Authors: Michael Glei, Sonja Fischer, Julia Lamberty, Diana Ludwig, Stefan Lorkowski, Wiebke SchlormannAbstract:BACKGROUND/AIM Due to their unique composition of health-promoting compounds, the consumption of hazelnuts may contribute to the prevention of Colon cancer. MATERIALS AND METHODS Since hazelnuts are often consumed roasted, the impact of different roasting conditions (RC1=140.6°C/25 min, RC2=155.1°C/20 min and RC3=180.4°C/21 min) on chemopreventive effects of in vitro fermented hazelnuts was analyzed in LT97 Colon Adenoma cells. RESULTS FS (2.5%) of raw and roasted hazelnuts reduced H2O2-induced DNA damage while 5% FS significantly induced gene expression of SOD2 (3.0-fold) and GSTP1 (2.1-fold). GPx1 mRNA levels were significantly decreased (0.6-fold) by FS (2.5%). The growth of LT97 cells was significantly reduced by hazelnut FS in a time- and dose-dependent manner. Hazelnut FS (5%) increased the numbers of early apoptotic cells (9.6% on average) and caspase-3 activities (6.4-fold on average). CONCLUSION These results indicate a chemopreventive potential of in vitro fermented hazelnuts which is largely unaffected by the roasting process.
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In vitro-fermented raw and roasted walnuts induce expression of CAT and GSTT2 genes, growth inhibition, and apoptosis in LT97 Colon Adenoma cells.
Nutrition research (New York N.Y.), 2017Co-Authors: Wiebke Schlormann, Diana Ludwig, Julia Lamberty, Stefan Lorkowski, Michael GleiAbstract:Walnuts are rich in bioactive compounds such as polyunsaturated fatty acids, polyphenols, and dietary fiber. Therefore, the consumption of walnuts can contribute to a healthy diet and may reduce the risk for Colon cancer. Heat treatment like roasting may change the chemical composition of walnuts and therefore their chemopreventive properties. Therefore, the hypothesis of the present study is that different roasting conditions (RCs) alter the chemopreventive effects of walnuts. Thus, the aim of the present study was to investigate whether different RCs (RC1=139.7°C/25 min, RC2=154.5°C/20 min, and RC3=185.5°C/25 min) alter the chemopreventive effects of walnuts. Raw and roasted walnuts were subjected to in vitro digestion and fermentation. After treatment of LT97 Colon Adenoma cells with fermentation supernatants (FSs), expression of CAT, SOD2, GPx1, GSTP1, and GSTT2 genes as well as cell growth and apoptosis was examined. In comparison to the fermentation blank control, walnut FS particularly increased mRNA levels of CAT 1.7-fold and GSTT2 3.1-fold, whereas GPx1 levels were significantly decreased 0.6-fold. Walnut FS decreased growth of Adenoma cells in a time- and dose-dependent manner. In particular, higher concentrations of walnut FS (5%) significantly increased the number of early apoptotic cells 2.0-fold and induced caspase-3 activity 6.8-fold compared with the blank control. The roasting process had no direct impact on the observed effects. In sum, our results indicate that walnuts exhibit chemopreventive effects regarding the risk for Colon cancer development by inducing expression of genes involved in detoxification (CAT, GSTT2) and by inducing growth inhibition and apoptosis in Colon Adenoma cells unaffected by moderate roasting.
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Influence of roasting on the chemopreventive potential of in vitro fermented almonds in LT97 Colon Adenoma cells.
International journal of food sciences and nutrition, 2017Co-Authors: Wiebke Schlormann, Sonja Fischer, Stefan Lorkowski, Christian Saupe, Tülin Dinc, Michael GleiAbstract:The consumption of almonds may contribute to the prevention of Colon cancer due to their unique composition of health promoting compounds. Since almonds are often consumed roasted, the impact of different roasting (R) conditions (R1 = 139.2 °C/25 min, R2 = 161.5 °C/20 min and R3 = 170.8 °C/15 min) on chemopreventive effects of in vitro-fermented almonds was analysed in LT97 Colon Adenoma cells. Fermentation supernatants (FS) of raw and roasted almonds had no genotoxic effects. FS obtained from raw or mildly roasted almonds (R1) significantly increased mRNA levels of CAT (4.6-fold), SOD2 (5.6-fold) and GSTP1 (3.9-fold) but not of GPx1. FS of almonds significantly reduced the growth of LT97 cells in a time- and dose-dependent manner. Treatment with 5% almonds FS increased the number of early apoptotic cells (17.4%, on average) and caspase-3 activity (4.9-fold, on average). The results indicate a chemopreventive potential of in vitro-fermented almonds which is largely independent of the roasting process.
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Chemopreventive potential of in vitro fermented nuts in LT97 Colon Adenoma and primary epithelial Colon cells.
Molecular carcinogenesis, 2017Co-Authors: Wiebke Schlormann, Julia Lamberty, Diana Ludwig, Stefan Lorkowski, Christian Saupe, Henning Mothes, Michael GleiAbstract:Due to their beneficial nutritional profile the consumption of nuts contributes to a healthy diet and might reduce Colon cancer risk. To get closer insights into potential mechanisms, the chemopreventive potential of different in vitro fermented nut varieties regarding the modulation of genes involved in detoxification (CAT, SOD2, GSTP1, GPx1) and cell cycle (p21, cyclin D2) as well as proliferation and apoptosis was examined in LT97 Colon Adenoma and primary epithelial Colon cells. Fermentation supernatants (FS) of nuts significantly induced mRNA expression of CAT (up to 4.0-fold), SOD2 (up to 2.5-fold), and GSTP1 (up to 2.3-fold), while GPx1 expression was significantly reduced by all nut FS (0.8 fold on average). Levels of p21 mRNA were significantly enhanced (up to 2.6-fold), whereas all nut FS significantly decreased cyclin D2 expression (0.4-fold on average). In primary epithelial cells, expression of CAT (up to 3.5-fold), GSTP1 (up to 3.0-fold), and GPx1 (up to 3.9-fold) was increased, whereas p21 and cyclin D2 levels were not influenced. Nut FS significantly inhibited growth of LT97 cells and increased levels of early apoptotic cells (8.4% on average) and caspase 3 activity (4.6-fold on average), whereas caspase 3 activity was not modulated in primary Colon cells. The differential modulation of genes involved in detoxification and cell cycle together with an inhibition of proliferation and induction of apoptosis in Adenoma cells might contribute to chemopreventive effects of nuts regarding Colon cancer.
Jeannette Bigler - One of the best experts on this subject based on the ideXlab platform.
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tissue specific patterns of gene expression in the epithelium and stroma of normal Colon in healthy individuals in an aspirin intervention trial
BMC Medical Genetics, 2015Co-Authors: Sushma S Thomas, Sanford D. Markowitz, Karen W Makar, Lin Li, Yingye Zheng, Peiying Yang, Lisa Levy, Rebecca Yvonne Rudolph, Paul D Lampe, Jeannette BiglerAbstract:Background Regular aspirin use reduces Colon Adenoma and carcinoma incidence. UDP-glucuronosyltransferases (UGT) are involved in aspirin metabolism and clearance, and variant alleles in UGT1A6 have been shown to alter salicylic acid metabolism and risk of Colon neoplasia.
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Tissue-specific patterns of gene expression in the epithelium and stroma of normal Colon in healthy individuals in an aspirin intervention trial
BMC Medical Genetics, 2015Co-Authors: Sushma S Thomas, Sanford D. Markowitz, Karen W Makar, Yingye Zheng, Peiying Yang, Lisa Levy, Rebecca Yvonne Rudolph, Paul D Lampe, Min Yan, Jeannette BiglerAbstract:Background Regular aspirin use reduces Colon Adenoma and carcinoma incidence. UDP-glucuronosyltransferases (UGT) are involved in aspirin metabolism and clearance, and variant alleles in UGT1A6 have been shown to alter salicylic acid metabolism and risk of Colon neoplasia. Methods In a randomized, cross-over, placebo-controlled trial of 44 healthy men and women, homozygous for UGT1A6*1 or UGT1A6*2, we explored differences between global epithelial and stromal expression, using Affymetrix U133 + 2.0 microarrays and tested effects of 60-day aspirin supplementation (325 mg/d) on epithelial and stromal gene expression and Colon prostaglandin E2 (PGE2) levels. Results No statistically significant differences in gene expression were observed in response to aspirin or UGT1A6 genotype, but tissue PGE2 levels were lower with aspirin compared to placebo (p
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cyp2c9 and ugt1a6 genotypes modulate the protective effect of aspirin on Colon Adenoma risk
Cancer Research, 2001Co-Authors: Jeannette Bigler, John Whitton, Johanna W Lampe, Lisa Fosdick, Roberd M Bostick, John D PotterAbstract:Regular use of nonsteroidal anti-inflammatory drugs (NSAIDs) has a protective effect on the incidence of Colon neoplasia. However, polymorphisms in NSAID-metabolizing enzymes may alter this effect. NSAIDs, particularly aspirin, are glucuronidated by UGT1A6 and some classes of NSAIDs are also metabolized by cytochrome P450 (CYP) 2C9. Both of these enzymes have slow-metabolizing, variant forms. We tested the hypothesis that the slow alleles of these enzymes can modify the inverse association between NSAIDs and Colon neoplasia in the Minnesota Cancer Prevention Research Unit (CPRU) Adenomatous polyp case-control study. CYP2C9 and UGT1A6 genotypes were determined for 474 Adenoma cases and 563 controls. NSAID use was inversely associated with Adenoma risk [odds ratio (OR), 0.63; 95% confidence interval (CI), 0.44-0.90 for aspirin; and OR, 0.50; 95% CI, 0.31-0.82 for nonaspirin NSAID]. However, this association was absent in aspirin users who carried the CYP2C9 variant alleles (OR, 0.88; 95% CI, 0.51-1.53) or who were homozygous wild-type UGT1A6 (OR, 0.86; 95% CI, 0.50-1.50). Carriers of both of these alleles who use aspirin were also not at reduced risk of Adenomatous polyps (OR, 1.59; 95% CI, 0.68-3.73). The variants of these enzymes did not influence the association between nonaspirin NSAIDs and Adenoma risk. These data indicate that the effectiveness of chemopreventive drugs can be modulated by the genotype of metabolizing enzymes.
James K V Willson - One of the best experts on this subject based on the ideXlab platform.
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Early loss of deleted in colorectal carcinoma gene transcript detected in a group of benign Colon Adenomas.
Journal of Biomedical Science, 2002Co-Authors: June L. Traicoff, James K V Willson, Sanford D. MarkowitzAbstract:We examined the expression of the putative tumor suppressor gene deleted in colorectal carcinoma (DCC) in human Colon Adenoma tissues and cell lines. One allele of DCC is deleted in 70% of human Colon carcinomas, and DCC expression is undetectable in 90% of Colon carcinoma cell lines. One DCC allele is also deleted in 50% of human Colon Adenomas, but results from protein expression studies have differed as to whether complete loss of DCC expression could occur in Colon Adenomas, or instead correlates with progression of Colon Adenoma to carcinoma. To further examine the timing of DCC expression loss in Colon Adenomas, we assayed DCC transcript levels in Adenoma cell lines and tissues. We measured DCC expression by a sensitive assay using Southern blot detection of the RT-PCR-amplified DCC transcript. DCC expression was negligible or greatly reduced in 4 of 14 Colon Adenomas, including 2 of 2 Adenoma cell lines and 2 of 12 Adenoma tissue samples. These data are the first evidence that expression of DCC transcript can be silenced in Colon Adenoma cell lines and tissues. These data indicate that loss of DCC expression occurs in some Colon Adenomas, but is insufficient to drive the Adenoma to carcinoma progression.
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transforming growth factor β induced growth inhibition in a smad4 mutant Colon Adenoma cell line
Cancer Research, 2001Co-Authors: Stephen P Fink, Sandra E Swinler, James Lutterbaugh, Joan Massague, Sam Thiagalingam, Kenneth W Kinzler, Bert Vogelstein, James K V WillsonAbstract:Transforming growth factor-beta (TGF-beta) inhibits growth and induces apoptosis of Colon epithelial cells. Binding of TGF-beta to its receptor induces phosphorylation of the Smad proteins Smad2 and Smad3, which then form heteromeric complexes with Smad4, translocate to the nucleus, and activate gene transcription. Smad4 function has been considered an obligate requirement for TGF-beta signaling, and Smad4 mutations present in some cancers have been considered sufficient to inactivate TGF-beta signaling. In this work, we describe studies with a nontransformed human Colon epithelial cell line that is mutant for Smad4 but remains growth-inhibited by TGF-beta. The Colon cell line VACO-235 has lost one of its Smad4 alleles via a chromosome 18q deletion. The remaining allele bears two missense point mutations located in regions important for Smad4 trimer formation, which is thought necessary for Smad4 function. As expected, pSBE4-BV/Luc, a Smad4-activated transcriptional reporter, was inactive in VACO-235. Nonetheless, VACO-235 demonstrated 80% growth inhibition in response to TGF-beta, as well as retention of some TGF-beta-mediated activation of the p3TP-Lux transcriptional reporter. Transient transfection of the VACO-235 Smad4 mutant allele into a Smad4-null cell line confirmed that this allele is functionally inactive as assayed by both the pSBE4-BV and p3TP-Lux reporters. The simplest explanation of these results is that there is a non-Smad4-dependent pathway for TGF-beta-mediated signaling and growth inhibition in VACO-235 cells.
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Both Transforming Growth Factor-β and Substrate Release Are Inducers of Apoptosis in a Human Colon Adenoma Cell Line
Cancer research, 1995Co-Authors: Cheng Ya Wang, James K V Willson, James R. Eshleman, Sanford D. MarkowitzAbstract:Abstract VACO-330, a nontransformed cell line established from a human Colon Adenoma, undergoes spontaneous apoptosis and shedding of cells into the culture medium. Shed cells were shown to be apoptotic, both by nuclear morphology and by generation of a typical “laddered” pattern of degraded DNA. Quantitation of DNA released into the medium, compared with the amount retained on the plate, demonstrated that 6.2 ± 1.1% of the total cell mass underwent apoptotic death daily. The addition of transforming growth factor β (20 ng/ml) accelerated this spontaneous apoptotic rate 3.2-fold. Moreover, apoptosis could be rapidly induced in up to 45% of the VACO-330 cells by using brief exposure to a calcium chelating medium to release the cells from the substratum. We suggest that transforming growth factor β is a likely physiological regulator of apoptosis during maturation of the Colonic epithelial cells. We additionally suggest the existence of an alternate pathway, which at the time of shedding from the crypt induces apoptosis in Colonic epithelial cells that have escaped earlier apoptotic signals.
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A benign cultured Colon Adenoma bears three genetically altered Colon cancer oncogenes, but progresses to tumorigenicity and transforming growth factor-beta independence without inactivating the p53 tumor suppressor gene.
The Journal of clinical investigation, 1994Co-Authors: Sanford D. Markowitz, Lois Myeroff, Mark J. Cooper, June L. Traicoff, Mary Kochera, I James Lutterbaugh, Margaret Swiriduk, James K V WillsonAbstract:We describe the spontaneous progression of a Colon Adenoma cell line to tumorigenicity and growth factor independence. This system allows direct comparison of biologic stages of malignant progression with alterations of Colon cancer suppressor genes and oncogenes. VACO-235, a human Colon Adenoma cell line, is at early passages nontumorigenic in the nude mouse, unable to grow in soft agar, growth stimulated by serum and EGF, and growth inhibited by TGF-beta. VACO-235 daughter passages 93 and higher have in culture spontaneously progressed to being weakly tumorigenic, but retain all other growth characteristics of VACO-235 early passages. A mouse xenograft from late passage VACO-235 was reestablished in culture as the granddaughter cell line, VACO-411. VACO-411 is highly tumorigenic, clones in soft agar, and is unresponsive to serum, EGF, and TGF-beta. Early passage VACO-235 bears a mutant K-ras allele, bears only mutant APC alleles, expresses no DCC transcripts, and expresses only wild type p53 transcripts. VACO-411 retains the identical genotype, still expressing only wild type p53. Colonic cells after ras mutation, APC mutation, and DCC inactivation remain nontumorigenic and growth factor dependent. Malignant progression involves at least two additional steps, and in VACO-411 can proceed by a novel pathway not requiring p53 inactivation.