[Modulation of colon cancer cell invasiveness induced by deoxycholic acid].
OBJECTIVE
Deoxycholic acid (DCA), a secondary bile acid, has been implicated to promote colon cancer growth and progression. However, its molecular mechanisms are largely unknown. In this study, we investigated the effects of DCA on proliferation, migration, and invasiveness of colon cancer cells (HT-29).


METHODS
HT-29 cells were incubated with either medium (control) only or DCA for 24-48 hours. Time courses of RT-PCR for vascular endothelial growth factor (VEGF) and hypoxia-inducible factor (HIF)-1alpha mRNA expression, Western blotting for VEGF and matrix metalloproteinase (MMP)-9, zymography for MMP-9 activation, and wound-migration assay were determined after various concentrations of DCA (0-80 microM) treatment. Moreover, these experiments were reassessed after pretreatments (2-6 hours) with specific inhibitors of various signal pathways.


RESULTS
DCA enhanced HIF-1alpha mRNA expression, VEGF mRNA and VEGF protein expression, MMP-9 protein expression/activation, and cell migration ability in a dose-related manner. DCA-induced VEGF protein expression was inhibited by pretreatment with NS-398 (COX-2 inhibitor), PDTC (NF-kappaB inhibitor), or tauroursodeoxycholic acid (TUDC). DCA-induced cell migration ability was inhibited by pretreatment of GF109203X, a protein kinase C inhibitor. DCA-induced MMP-9 protein expression/activation was inhibited by pretreatment with SB203580, U0126, or PDTC.


CONCLUSIONS
DCA significantly upregulates invasive and angiogenic potentials of human colon cancer cells through multiple signal transduction pathways.
Kim
Hyun Soo
HS
Department of Internal Medicine, Yonsei University Wonju College of Medicine, Wonju, Korea. hyskim@yonsei.ac.kr
Lee
Yong Kyu
YK
Kim
Jae Woo
JW
Baik
Soon Koo
SK
Kwon
Sang Ok
SO
Jang
Hwa In
HI
D002465:Cell Movement / Q000187:drug effects; D003110:Colonic Neoplasms / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology*; D003840:Deoxycholic Acid / Q000494:pharmacology*; D019073:HT29 Cells; D006801:Humans; D051793:Hypoxia-Inducible Factor 1 / Q000378:metabolism; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism; D009361:Neoplasm Invasiveness; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000187:drug effects; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism
D051793:Hypoxia-Inducible Factor 1; D042461:Vascular Endothelial Growth Factor A; D003840:Deoxycholic Acid; D020780:Matrix Metalloproteinase 9