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  • 1
    Online Resource
    Online Resource
    GPR109A Is a G-protein–Coupled Receptor for the Bacterial Fermentation Product Butyrate and Functions as a Tumor Suppressor in Colon
    American Association for Cancer Research (AACR) ; 2009
    In:  Cancer Research Vol. 69, No. 7 ( 2009-04-01), p. 2826-2832
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 69, No. 7 ( 2009-04-01), p. 2826-2832
    Abstract: Short-chain fatty acids, generated in colon by bacterial fermentation of dietary fiber, protect against colorectal cancer and inflammatory bowel disease. Among these bacterial metabolites, butyrate is biologically most relevant. GPR109A is a G-protein–coupled receptor for nicotinate but recognizes butyrate with low affinity. Millimolar concentrations of butyrate are needed to activate the receptor. Although concentrations of butyrate in colonic lumen are sufficient to activate the receptor maximally, there have been no reports on the expression/function of GPR109A in this tissue. Here we show that GPR109A is expressed in the lumen-facing apical membrane of colonic and intestinal epithelial cells and that the receptor recognizes butyrate as a ligand. The expression of GPR109A is silenced in colon cancer in humans, in a mouse model of intestinal/colon cancer, and in colon cancer cell lines. The tumor-associated silencing of GPR109A involves DNA methylation directly or indirectly. Reexpression of GPR109A in colon cancer cells induces apoptosis, but only in the presence of its ligands butyrate and nicotinate. Butyrate is an inhibitor of histone deacetylases, but apoptosis induced by activation of GPR109A with its ligands in colon cancer cells does not involve inhibition of histone deacetylation. The primary changes in this apoptotic process include down-regulation of Bcl-2, Bcl-xL, and cyclin D1 and up-regulation of death receptor pathway. In addition, GPR109A/butyrate suppresses nuclear factor-κB activation in normal and cancer colon cell lines as well as in normal mouse colon. These studies show that GPR109A mediates the tumor-suppressive effects of the bacterial fermentation product butyrate in colon. [Cancer Res 2009;69(7):2826–32]
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    URL: Article
    DOI: 10.1158/0008-5472.CAN-08-4466
    RVK:
    XA 36000
    RVK:
    XA 10000
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2009
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  • 2
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    Sodium-Coupled Transport of the Short Chain Fatty Acid Butyrate by SLC5A8 and Its Relevance to Colon Cancer
    Elsevier BV ; 2008
    In:  Journal of Gastrointestinal Surgery Vol. 12, No. 10 ( 2008-10), p. 1773-1782
    Details
    In: Journal of Gastrointestinal Surgery, Elsevier BV, Vol. 12, No. 10 ( 2008-10), p. 1773-1782
    Type of Medium: Online Resource
    ISSN: 1091-255X , 1873-4626
    URL: Article
    DOI: 10.1007/s11605-008-0573-0
    Language: English
    Publisher: Elsevier BV
    Publication Date: 2008
    detail.hit.zdb_id: 2057634-1
    detail.hit.zdb_id: 2012365-6
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  • 3
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    IFNγ Induces DNA Methylation–Silenced GPR109A Expression via pSTAT1/p300 and H3K18 Acetylation in Colon Cancer
    American Association for Cancer Research (AACR) ; 2015
    In:  Cancer Immunology Research Vol. 3, No. 7 ( 2015-07-01), p. 795-805
    Details
    In: Cancer Immunology Research, American Association for Cancer Research (AACR), Vol. 3, No. 7 ( 2015-07-01), p. 795-805
    Abstract: Short-chain fatty acids, metabolites produced by colonic microbiota from fermentation of dietary fiber, act as anti-inflammatory agents in the intestinal tract to suppress proinflammatory diseases. GPR109A is the receptor for short-chain fatty acids. The functions of GPR109A have been the subject of extensive studies; however, the molecular mechanisms underlying GPR109A expression is largely unknown. We show that GPR109A is highly expressed in normal human colon tissues, but is silenced in human colon carcinoma cells. The GPR109A promoter DNA is methylated in human colon carcinoma. Strikingly, we observed that IFNγ, a cytokine secreted by activated T cells, activates GPR109A transcription without altering its promoter DNA methylation. Colon carcinoma grows significantly faster in IFNγ-deficient mice than in wild-type mice in an orthotopic colon cancer mouse model. A positive correlation was observed between GPR109A protein level and tumor-infiltrating T cells in human colon carcinoma specimens, and IFNγ expression level is higher in human colon carcinoma tissues than in normal colon tissues. We further demonstrated that IFNγ rapidly activates pSTAT1 that binds to the promoter of p300 to activate its transcription. p300 then binds to the GPR109A promoter to induce H3K18 hyperacetylation, resulting in chromatin remodeling in the methylated GPR109A promoter. The IFNγ-activated pSTAT1 then directly binds to the methylated but hyperacetylated GPR109 promoter to activate its transcription. Overall, our data indicate that GPR109A acts as a tumor suppressor in colon cancer, and the host immune system might use IFNγ to counteract DNA methylation–mediated GPR109A silencing as a mechanism to suppress tumor development. Cancer Immunol Res; 3(7); 795–805. ©2015 AACR.
    Type of Medium: Online Resource
    ISSN: 2326-6066 , 2326-6074
    URL: Article
    DOI: 10.1158/2326-6066.CIR-14-0164
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2015
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  • 4
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    SIRT1 Is Essential for Oncogenic Signaling by Estrogen/Estrogen Receptor α in Breast Cancer
    American Association for Cancer Research (AACR) ; 2011
    In:  Cancer Research Vol. 71, No. 21 ( 2011-11-01), p. 6654-6664
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 71, No. 21 ( 2011-11-01), p. 6654-6664
    Abstract: The NAD-dependent histone deacetylase silent information regulator 1 (SIRT1) is overexpressed and catalytically activated in a number of human cancers, but recent studies have actually suggested that it may function as a tumor suppressor and metastasis inhibitor in vivo. In breast cancer, SIRT1 stabilization has been suggested to contribute to the oncogenic potential of the estrogen receptor α (ERα), but SIRT1 activity has also been associated with ERα deacetylation and inactivation. In this study, we show that SIRT1 is critical for estrogen to promote breast cancer. ERα physically interacted and functionally cooperated with SIRT1 in breast cancer cells. ERα also bound to the promoter for SIRT1 and increased its transcription. SIRT1 expression induced by ERα was sufficient to activate antioxidant and prosurvival genes in breast cancer cells, such as catalase and glutathione peroxidase, and to inactivate tumor suppressor genes such as cyclin G2 (CCNG2) and p53. Moreover, SIRT1 inactivation eliminated estrogen/ERα-induced cell growth and tumor development, triggering apoptosis. Taken together, these results indicated that SIRT1 is required for estrogen-induced breast cancer growth. Our findings imply that the combination of SIRT1 inhibitors and antiestrogen compounds may offer more effective treatment strategies for breast cancer. Cancer Res; 71(21); 6654–64. ©2011 AACR.
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    URL: Article
    DOI: 10.1158/0008-5472.CAN-11-1446
    RVK:
    XA 36000
    RVK:
    XA 10000
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2011
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    detail.hit.zdb_id: 1432-1
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  • 5
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    Online Resource
    Repression of IFN Regulatory Factor 8 by DNA Methylation Is a Molecular Determinant of Apoptotic Resistance and Metastatic Phenotype in Metastatic Tumor Cells
    American Association for Cancer Research (AACR) ; 2007
    In:  Cancer Research Vol. 67, No. 7 ( 2007-04-01), p. 3301-3309
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 67, No. 7 ( 2007-04-01), p. 3301-3309
    Abstract: Apoptotic resistance is often associated with metastatic phenotype in tumor cells and is considered a hallmark of tumor progression. In this study, IFN regulatory factor 8 (IRF8) expression was found to be inversely correlated with an apoptotic-resistant and metastatic phenotype in human colon carcinoma cell lines in vitro. This inverse correlation was further extended to spontaneously arising primary mammary carcinoma and lung metastases in a mouse tumor model in vivo. Exogenous expression of IRF8 in the metastatic tumor cell line restored, at least partially, the sensitivity of the tumor cells to Fas-mediated apoptosis, and disruption of IRF8 function conferred the poorly metastatic tumors with enhanced apoptotic resistance and metastatic capability. DNA demethylation restored IRF8 expression and sensitized the metastatic tumor cells to Fas-mediated apoptosis. Analysis of genomic DNA isolated from both primary and metastatic tumor cells with methylation-sensitive PCR revealed hypermethylation of the IRF8 promoter in metastatic tumor cells but not in primary tumor cells. Taken together, our data suggest that IRF8 is both an essential regulator in Fas-mediated apoptosis pathway and a metastasis suppressor in solid tumors and that metastatic tumor cells use DNA hypermethylation to repress IRF8 expression to evade apoptotic cell death and to acquire a metastatic phenotype. [Cancer Res 2007;67(7):3301–9]
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    URL: Article
    DOI: 10.1158/0008-5472.CAN-06-4068
    RVK:
    XA 36000
    RVK:
    XA 10000
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2007
    detail.hit.zdb_id: 2036785-5
    detail.hit.zdb_id: 1432-1
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  • 6
    Online Resource
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    Cyclic 3′,5′-guanosine monophosphate-dependent protein kinase inhibits colon cancer cell adaptation to hypoxia
    Wiley ; 2011
    In:  Cancer Vol. 117, No. 23 ( 2011-12-01), p. 5282-5293
    Details
    In: Cancer, Wiley, Vol. 117, No. 23 ( 2011-12-01), p. 5282-5293
    Type of Medium: Online Resource
    ISSN: 0008-543X
    URL: Issue
    URL: Article
    DOI: 10.1002/cncr.v117.23
    DOI: 10.1002/cncr.26192
    Language: English
    Publisher: Wiley
    Publication Date: 2011
    detail.hit.zdb_id: 1429-1
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  • 7
    Online Resource
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    Interferon Regulatory Factor 8 Mediates Apoptosis via Regulation of Fas and FLIP Expression
    Wiley ; 2008
    In:  The FASEB Journal Vol. 22, No. S1 ( 2008-03)
    Details
    In: The FASEB Journal, Wiley, Vol. 22, No. S1 ( 2008-03)
    Abstract: IRF8 is a transcription factor that was originally identified in myeloid cells. Mice with a null mutation of IRF8 exhibit uncontrolled expansion of myeloid cells that progress into a phenotype resembling human chronic myelogenous leukemia (CML). In human patients with CML, IRF8 transcript levels are frequently diminished. Here, we report that disruption of IRF8 function diminished Fas‐mediated apoptosis in solid tumor cells. Furthermore, it was found that constitutively expressed IRF8 is associated with the Fas promoter to activate Fas transcription. In addition, disruption of constitutively expressed IRF8 function diminished JAK1 expression and thereby inhibited IFNγ‐initiated induction of STAT1 phosphorylation. Interestingly, the constitutively expressed IRF8 was also essential for TNF‐α‐sensitization of Fas‐mediated apoptosis since disruption of IRF8 function also inhibited TNFα‐sensitized and Fas‐mediated apoptosis. Analysis of IRF8‐deficient dendritic cells (DC) generated from IRF8 null mice revealed that Fas expression level is also down‐regulated as compared to the wild type mice. In addition, IRF8‐deficient DCs also exhibited higher level of FLIPs protein as compared to the control wt DCs. Taken together, our data suggest that IRF8 is an essential regulator of Fas‐mediated apoptosis and that IRF8 mediates apoptosis through regulation of Fas and FLIP.
    Type of Medium: Online Resource
    ISSN: 0892-6638 , 1530-6860
    URL: Issue
    URL: Article
    DOI: 10.1096/fsb2.v22.S1
    DOI: 10.1096/fasebj.22.1_supplement.1079.9
    Language: English
    Publisher: Wiley
    Publication Date: 2008
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    SSG: 12
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  • 8
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    Online Resource
    IFN Regulatory Factor 8 Mediates Apoptosis in Nonhemopoietic Tumor Cells via Regulation of Fas Expression
    The American Association of Immunologists ; 2007
    In:  The Journal of Immunology Vol. 179, No. 7 ( 2007-10-01), p. 4775-4782
    Details
    In: The Journal of Immunology, The American Association of Immunologists, Vol. 179, No. 7 ( 2007-10-01), p. 4775-4782
    Abstract: IFN regulatory factor 8 (IRF8) is a transcription factor that was originally identified in myeloid cells and has been shown to be essential for differentiation and function of hemopoietic cells. Mice with a null mutation of IRF8 exhibit uncontrolled expansion of the granulocytic and monocytic lineages that progress into a phenotype resembling human chronic myelogenous leukemia. In human patients with chronic myelogenous leukemia, IRF8 transcript levels are frequently diminished. Therefore, IRF8 is a key regulator of myeloid tumor development. In this study, we report that IRF8 is a critical regulator of apoptosis in nonhemopoietic tumor cells. Disruption of IRF8 function with IRF8 dominant-negative mutants diminished Fas-mediated apoptosis in sarcoma tumor cells. Both constitutively expressed and IFN-γ-activated IRF8 were involved in regulation of apoptosis. Furthermore, it was found that constitutively expressed IRF8 is associated with the Fas promoter to activate Fas transcription. In addition, disruption of constitutively expressed IRF8 function diminished JAK1 expression and thereby inhibited IFN-γ-initiated induction of STAT1 phosphorylation, which in turn, blocked IFN-γ-induced Fas up-regulation. Interestingly, the constitutively expressed IRF8 was also essential for TNF-α sensitization of Fas-mediated apoptosis because disruption of IRF8 function also inhibited TNF-α-sensitized and Fas-mediated apoptosis. Taken together, our data suggest that IRF8 is an essential mediator of Fas-mediated apoptosis and that IRF8 mediates apoptosis through regulation of Fas expression in nonhemopoietic tumor cells.
    Type of Medium: Online Resource
    ISSN: 0022-1767 , 1550-6606
    URL: Article
    DOI: 10.4049/jimmunol.179.7.4775
    RVK:
    XA 54100
    RVK:
    XA 10000
    Language: English
    Publisher: The American Association of Immunologists
    Publication Date: 2007
    detail.hit.zdb_id: 1475085-5
    detail.hit.zdb_id: 3056-9
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  • 9
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    Type 2 cGMP-dependent protein kinase regulates proliferation and differentiation in the colonic mucosa
    American Physiological Society ; 2012
    In:  American Journal of Physiology-Gastrointestinal and Liver Physiology Vol. 303, No. 2 ( 2012-07-15), p. G209-G219
    Details
    In: American Journal of Physiology-Gastrointestinal and Liver Physiology, American Physiological Society, Vol. 303, No. 2 ( 2012-07-15), p. G209-G219
    Abstract: Signaling through cGMP has emerged as an important regulator of tissue homeostasis in the gastrointestinal tract, but the mechanism is not known. Type 2 cGMP-dependent protein kinase (PKG2) is a major cGMP effector in the gut epithelium, and the present studies have tested its importance in the regulation of proliferation and differentiation in the mouse colon and in colon cancer cell lines. Tissue homeostasis was examined in the proximal colon of Prkg2 −/− mice using histological markers of proliferation and differentiation. The effect of ectopic PKG2 on proliferation and differentiation was tested in vitro using inducible colon cancer cell lines. PCR and luciferase reporter assays were used to determine the importance of Sox9 downstream of PKG2. The colons of Prkg2 −/− mice exhibited crypt hyperplasia, increased epithelial apoptosis, and reduced numbers of differentiated goblet and enteroendocrine cells. Ectopic PKG2 was able to inhibit proliferation and induce Muc2 and CDX2 expression in colon cancer cells, but did not significantly affect cell death. PKG2 reduced Sox9 levels and signaling, suggesting possible involvement of this pathway downstream of cGMP in the colon. The work presented here demonstrates a novel antiproliferative and prodifferentiation role for PKG2 in the colon. These homeostatic functions of PKG2 were reproducible in colon cancer cells lines where downregulation of Sox9 is a possible mechanism. The similarities in phenotype between PKG2 and GCC knockout mice positions PKG2 as a likely mediator of the homeostatic effects of cGMP signaling in the colon.
    Type of Medium: Online Resource
    ISSN: 0193-1857 , 1522-1547
    URL: Article
    DOI: 10.1152/ajpgi.00500.2011
    Language: English
    Publisher: American Physiological Society
    Publication Date: 2012
    detail.hit.zdb_id: 1477329-6
    detail.hit.zdb_id: 603840-2
    SSG: 12
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  • 10
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    Abstract 4106: Curcumin inhibit PhIP induced cytotoxicity by inhibiting ROS production, DNA strand breaks and DNA adducts formation in MCF 10A cells
    American Association for Cancer Research (AACR) ; 2014
    In:  Cancer Research Vol. 74, No. 19_Supplement ( 2014-10-01), p. 4106-4106
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 74, No. 19_Supplement ( 2014-10-01), p. 4106-4106
    Abstract: PhIP is a known food carcinogen found in well done meat which causes several cancers including breast cancer. PhIP metabolites produce DNA adduct and DNA strand breaks. Curcumin, obtained from the rhizome of Curcuma longa, has potent anticancer activity. So far none of the study demonstrates the inhibition of PhIP induced cytotoxicity by the co-treatment of Curcumin in normal breast epithelial cells in vitro. Therefore, we developed a model system using the MCF 10A normal breast epithelial cells to study the PhIP cytotoxicity and if cells are co-cultured with Curcumin and PhIP how it affects. Consequently, the core signaling pathways have been explored to evaluate the efficacy of Curcumin. In this study, the effectiveness of Curcumin was investigated in MCF 10A cells along with PhIP. The cytotoxic ability was detected with MTT assay, ROS activation by DCF, the influence of the cell cycle was checked with flow cytometry, DNA damage by comet assay, DNA adduct formation by anti-PhIP DNA primary, and apoptosis by Annexin-V-FITC staining. The influence of the core signaling pathways was evaluated by RT PCR and/or Western blotting which included Nrf2 (GSR, GPX, NQO1), FOXO (Catalase, GADD45, PRDX3) targets; DNA repair genes/proteins BRCA1, H2AFX and PARP-1; and tumor suppressor P16 gene expression. PhIP cytotoxicity induced the expression of various antioxidant and DNA repair genes on MCF-10A cells but co-treatment of Curcumin retained its expression level similar to untreated groups. Additionally, Curcumin co- treatment increased the expression level of tumor suppressor expression gene P-53. Expression of antioxidants genes was induced by PhIP whereas Curcumin significantly suppress the PhIP induced ROS activation, DNA strand breaks and DNA adduct formation and consequently inhibited the cell death. In conclusion, Curcumin appears to be effective to inhibit P450 mediated ROS production and PhIP-DNA adducts which consequently reduces DNA damage. Citation Format: Ashok K. Jain, Abhilash Samykutty, Carissa L. Jackson, Muthusamy Thangaraju, Darren D. Browning. Curcumin inhibit PhIP induced cytotoxicity by inhibiting ROS production, DNA strand breaks and DNA adducts formation in MCF 10A cells. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 4106. doi:10.1158/1538-7445.AM2014-4106
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    URL: Article
    DOI: 10.1158/1538-7445.AM2014-4106
    RVK:
    XA 36000
    RVK:
    XA 10000
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2014
    detail.hit.zdb_id: 2036785-5
    detail.hit.zdb_id: 1432-1
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