Submitted to: American Association of Cancer Research Meeting
Publication Type: Abstract Only
Publication Acceptance Date: December 1, 2008
Publication Date: February 10, 2009
Citation: Zeng, H., Botnen, J.H., Briske Anderson, M.J. 2009. Differential effects of deoxycholic acid versus selenium metabolite methylselenol on cell cycle, apoptosis, and MAP kinase pathway in HCT116 human colon cancer cells. American Association of Cancer Research Meeting. Published in Abstracts of Poster Presentations. No. 4. Technical Abstract: Introduction: A typical part of the Western diet is a high fat intake that leads to increased levels of fecal bile acids, and these bile acids, primarily deoxycholic acid (DCA) in humans, have been believed to be tumor promoters of colon cancer. The cell growth inhibition induced by bile acid deoxycholic acid (DCA) may cause compensatory hyperproliferation of colonic epithelial cells and provide selection for subpopulations of cells resistant to DCA’s inhibitory effect. These surviving cells are somehow mutated and are resistant to the bile acid, and consequently increase colon cancer risk. On the other hand, there is increasing evidence for the efficacy of certain forms of selenium (Se) as cancer-chemopreventive compounds. Methylselenol has been hypothesized to be a critical selenium metabolite for anticancer activity in vivo. Methods: The exclusion of trypan blue dye and flow cytometry of propidium iodide-stained nuclei were used to monitor DCA and Se-regulated changes in HCT116 human colon cancer cell proliferation and cell cycle progression, and cell apoptosis was analyzed by using a Guava NexinTM Kit. In addition, an array of mitogen-activated protein kinase (MAPK) antibody was employed to characterize the MAP kinase pathway. Results: In this study, we demonstrated that, both DCA (75 - 300 micromol/L) and methylselenol generated by incubating 40 U/L methioninase (METase) with 1.25 - 5 micromol/L seleno-L-methionine (SeMet), inhibited colon cancer cell proliferation by up to 64% and 63%, respectively. In addition, DCA and methylselenol each increased colon cancer cell apoptosis rate by up to 2-fold. Cell cycle analyses revealed that DCA led an increase in only the G1 fraction with a concomitant drop in G2 and S-phase; in contrast, methylselenol led to an increase in the G1 and G2 fractions with a concomitant drop only in the S-phase. Although both DCA and methylselenol significantly promoted apoptosis and inhibited cell growth, an array of mitogen-activated protein kinase (MAPK) antibody analysis showed that DCA, but not methylselenol, induced SAPK/JNK1/2, p38 MAPK, ERK1/2 activation. Conclusions: These results demonstrate that deoxycholic acid and selenium metabolite methylselenol exert common and distinct effects on cell cycle, apoptosis, and MAP kinase pathway in HCT116 human colon cancer cells. Thus, our data provide, for the first time, the molecular basis for opposite effects of methylselenol and DCA on colon tumorigenesis.