Bile acids induce MUC2 overexpression in human colon carcinoma cells.
BACKGROUND
Mucin alterations are a common feature of colonic neoplasia, and alterations in MUC2 mucin have been associated with tumor progression in the colon. Bile acids have been linked to colorectal carcinogenesis and mucin secretion, but their effects on mucin gene expression in human colon carcinoma cells is unknown


METHODS
Human colon carcinoma cells were treated </= 6 hours with 10-200 microM deoxycholate, chenodeoxycholate, or ursodeoxycholate. MUC2 protein was assayed by Western blot analysis and MUC2 transcription was assayed using a MUC2 promoter reporter luciferase construct. Transcription activator protein 1 (AP-1) activity was measured using an AP-1 reporter construct and confirmed by Western blot analysis for c-Jun/AP-1.


RESULTS
MUC2 transcription and MUC2 protein expression were increased three to fourfold by bile acids in a time and dose-dependent manner with no effect on cell viability. AP-1 activity was also increased (deoxycholate > chenodeoxycholate > ursodeoxycholate). Treatment with the putative chemopreventive agent curcumin, which decreased AP-1 activity, also decreased MUC2 transcription. Cotransfection with a dominant negative AP-1 vector decreased MUC2 transcription, confirming the significance of AP-1 in MUC2 induction by deoxycholate. Calphostin C, a specific inhibitor of protein kinase C (PKC), greatly decreased bile acid-induced MUC2 transcription and AP-1 activity, whereas inhibitors of MAP kinase had no effect.


CONCLUSIONS
Bile acids induced mucin expression in human colon carcinoma cells by increasing MUC2 transcription through a process involving MAP kinase-independent, PKC-dependent activation of AP-1.
Song
Shumei
S
Department of Gastrointestinal Medicine and Nutrition, The University of Texas M. D. Anderson Cancer Center, Houston, Texas 77030-4009, USA.
Byrd
James C
JC
Koo
Ja Seok
JS
Bresalier
Robert S
RS
D000970:Antineoplastic Agents / Q000494:pharmacology; D002635:Chenodeoxycholic Acid / Q000494:pharmacology; D002756:Cholagogues and Choleretics / Q000494:pharmacology*; D002793:Cholic Acids / Q000494:pharmacology*; D003110:Colonic Neoplasms / Q000378:metabolism* / Q000473:pathology; D003474:Curcumin / Q000494:pharmacology; D003840:Deoxycholic Acid / Q000494:pharmacology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects*; D006801:Humans; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D055262:Mucin-2; D009077:Mucins / Q000235:genetics* / Q000378:metabolism; D009281:Naphthalenes / Q000494:pharmacology; D011401:Promoter Regions, Genetic / Q000235:genetics; D011493:Protein Kinase C / Q000037:antagonists & inhibitors / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D018808:Transcription Factor AP-1 / Q000235:genetics; D014158:Transcription, Genetic / Q000187:drug effects; D015533:Transcriptional Activation; D014407:Tumor Cells, Cultured; D015854:Up-Regulation; D014580:Ursodeoxycholic Acid / Q000494:pharmacology
D000970:Antineoplastic Agents; D002756:Cholagogues and Choleretics; D002793:Cholic Acids; D004791:Enzyme Inhibitors; C524625:MUC2 protein, human; D055262:Mucin-2; D009077:Mucins; D009281:Naphthalenes; D012333:RNA, Messenger; D018808:Transcription Factor AP-1; D003840:Deoxycholic Acid; D002635:Chenodeoxycholic Acid; D014580:Ursodeoxycholic Acid; D011493:Protein Kinase C; D020928:Mitogen-Activated Protein Kinases; C058819:calphostin C; D003474:Curcumin