Deoxycholate promotes survival of breast cancer cells by reducing the level of pro-apoptotic ceramide.

Hdl Handle:
http://hdl.handle.net/10675.2/65
Title:
Deoxycholate promotes survival of breast cancer cells by reducing the level of pro-apoptotic ceramide.
Authors:
Krishnamurthy, Kannan; Wang, Guanghu; Rokhfeld, Dmitriy; Bieberich, Erhard
Abstract:
INTRODUCTION: At physiologic concentration in serum, the bile acid sodium deoxycholate (DC) induces survival and migration of breast cancer cells. Here we provide evidence of a novel mechanism by which DC reduces apoptosis that is induced by the sphingolipid ceramide in breast cancer cells. METHODS: Murine mammacarcinoma 4T1 cells were used in vitro to determine apoptosis and alteration of sphingolipid metabolism by DC, and in vivo to quantify the effect of DC on metastasis. RESULTS: We found that DC increased the number of intestinal metastases generated from 4T1 cell tumors grafted into the fat pad. The metastatic nodes contained slowly dividing cancer cells in immediate vicinity of newly formed blood vessels. These cells were positive for CD44, a marker that has been suggested to be expressed on breast cancer stem cells. In culture, a subpopulation (3 +/- 1%) of slowly dividing, CD44+ cells gave rise to rapidly dividing, CD44- cells. DC promoted survival of CD44+ cells, which was concurrent with reduced levels of activated caspase 3 and ceramide, a sphingolipid inducing apoptosis in 4T1 cells. Z-guggulsterone, an antagonist of the farnesoid-X-receptor, obliterated this anti-apoptotic effect, indicating that DC increased cell survival via farnesoid-X-receptor. DC also increased the gene expression of the vascular endothelial growth factor receptor 2 (Flk-1), suggesting that DC enhanced the initial growth of secondary tumors adjacent to blood vessels. The Flk-1 antagonist SU5416 obliterated the reduction of ceramide and apoptosis by DC, indicating that enhanced cell survival is due to Flk-1-induced reduction in ceramide. CONCLUSIONS: Our findings show, for the first time, that DC is a natural tumor promoter by elevating Flk-1 and decreasing ceramide-mediated apoptosis of breast cancer progenitor cells. Reducing the level or effect of serum DC and elevating ceramide in breast cancer progenitor cells by treatment with Z-guggulsterone and/or vascular endothelial growth factor receptor 2/Flk-1 antagonists may thus be a promising strategy to reduce breast cancer metastasis.
Citation:
Breast Cancer Res. 2008 Dec 16; 10(6):R106
Issue Date:
23-Feb-2009
URI:
http://hdl.handle.net/10675.2/65
DOI:
10.1186/bcr2211
PubMed ID:
19087284
PubMed Central ID:
PMC2656903
Type:
Journal Article; Research Support, Non-U.S. Gov't
ISSN:
1465-542X
Appears in Collections:
Institute of Molecular Medicine and Genetics: Faculty Research and Presentations

Full metadata record

DC FieldValue Language
dc.contributor.authorKrishnamurthy, Kannanen_US
dc.contributor.authorWang, Guanghuen_US
dc.contributor.authorRokhfeld, Dmitriyen_US
dc.contributor.authorBieberich, Erharden_US
dc.date.accessioned2010-09-24T21:26:50Z-
dc.date.available2010-09-24T21:26:50Z-
dc.date.issued2009-02-23en_US
dc.identifier.citationBreast Cancer Res. 2008 Dec 16; 10(6):R106en_US
dc.identifier.issn1465-542Xen_US
dc.identifier.pmid19087284en_US
dc.identifier.doi10.1186/bcr2211en_US
dc.identifier.urihttp://hdl.handle.net/10675.2/65-
dc.description.abstractINTRODUCTION: At physiologic concentration in serum, the bile acid sodium deoxycholate (DC) induces survival and migration of breast cancer cells. Here we provide evidence of a novel mechanism by which DC reduces apoptosis that is induced by the sphingolipid ceramide in breast cancer cells. METHODS: Murine mammacarcinoma 4T1 cells were used in vitro to determine apoptosis and alteration of sphingolipid metabolism by DC, and in vivo to quantify the effect of DC on metastasis. RESULTS: We found that DC increased the number of intestinal metastases generated from 4T1 cell tumors grafted into the fat pad. The metastatic nodes contained slowly dividing cancer cells in immediate vicinity of newly formed blood vessels. These cells were positive for CD44, a marker that has been suggested to be expressed on breast cancer stem cells. In culture, a subpopulation (3 +/- 1%) of slowly dividing, CD44+ cells gave rise to rapidly dividing, CD44- cells. DC promoted survival of CD44+ cells, which was concurrent with reduced levels of activated caspase 3 and ceramide, a sphingolipid inducing apoptosis in 4T1 cells. Z-guggulsterone, an antagonist of the farnesoid-X-receptor, obliterated this anti-apoptotic effect, indicating that DC increased cell survival via farnesoid-X-receptor. DC also increased the gene expression of the vascular endothelial growth factor receptor 2 (Flk-1), suggesting that DC enhanced the initial growth of secondary tumors adjacent to blood vessels. The Flk-1 antagonist SU5416 obliterated the reduction of ceramide and apoptosis by DC, indicating that enhanced cell survival is due to Flk-1-induced reduction in ceramide. CONCLUSIONS: Our findings show, for the first time, that DC is a natural tumor promoter by elevating Flk-1 and decreasing ceramide-mediated apoptosis of breast cancer progenitor cells. Reducing the level or effect of serum DC and elevating ceramide in breast cancer progenitor cells by treatment with Z-guggulsterone and/or vascular endothelial growth factor receptor 2/Flk-1 antagonists may thus be a promising strategy to reduce breast cancer metastasis.en_US
dc.rightsThe PMC Open Access Subset is a relatively small part of the total collection of articles in PMC. Articles in the PMC Open Access Subset are still protected by copyright, but are made available under a Creative Commons or similar license that generally allows more liberal redistribution and reuse than a traditional copyrighted work. Please refer to the license statement in each article for specific terms of use. The license terms are not identical for all articles in this subset.en_US
dc.subject.meshAnimalsen_US
dc.subject.meshAntigens, CD44en_US
dc.subject.meshApoptosis / drug effectsen_US
dc.subject.meshBlotting, Westernen_US
dc.subject.meshCell Survival / drug effectsen_US
dc.subject.meshCeramides / metabolismen_US
dc.subject.meshCholagogues and Choleretics / pharmacologyen_US
dc.subject.meshChromatography, Thin Layeren_US
dc.subject.meshDeoxycholic Acid / pharmacologyen_US
dc.subject.meshFemaleen_US
dc.subject.meshFlow Cytometryen_US
dc.subject.meshImmunoenzyme Techniquesen_US
dc.subject.meshMammary Neoplasms, Experimental / drug therapy / metabolism / pathologyen_US
dc.subject.meshMiceen_US
dc.subject.meshMice, Inbred BALB Cen_US
dc.subject.meshRNA, Messenger / genetics / metabolismen_US
dc.subject.meshReverse Transcriptase Polymerase Chain Reactionen_US
dc.subject.meshSphingolipids / metabolismen_US
dc.subject.meshTumor Cells, Cultureden_US
dc.subject.meshVascular Endothelial Growth Factor Receptor-2en_US
dc.titleDeoxycholate promotes survival of breast cancer cells by reducing the level of pro-apoptotic ceramide.en_US
dc.typeJournal Articleen_US
dc.typeResearch Support, Non-U.S. Gov'ten_US
dc.identifier.pmcidPMC2656903en_US
dc.contributor.corporatenameInstitute of Molecular Medicine and Geneticsen_US
dc.contributor.corporatenameStudent Research and Training (STAR) Program, School of Graduate Studiesen_US

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