Submitted to: Journal of Nutritional Biochemistry
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 4/13/2013
Publication Date: 7/27/2012
Citation: Zeng, H., Cheng, W., Johnson, L.K. 2012. Methylselenol, a selenium metabolite, modulates p53 pathway and inhibits the growth of MC-26 colon cancer xenografts in balb/c mice. Journal of Nutritional Biochemistry. DOI:10.1016/j.nutbio.2012.04.008. Interpretive Summary: Epidemiological evidence indicates that selenium status is inversely associated with cancer risk, and results from intervention studies show that high Se intakes effectively reduce the risk of mammary, prostate, lung, colon, and liver cancer. Methylselenol, a selenium metabolite, has been hypothesized to be a critical selenium (Se) metabolite for anticancer activity in vivo. Recently, we have found that methylselenol’s stronger potential of inhibiting cell proliferation / survival signals in cancerous cells when compared with that in noncancerous cells. However, the molecular mechanism(s) for these effects still remain to be characterized. In this study, our data demonstrate that methylselenol inhibited cell growth and led to an increase in G1 and G2 fractions with a concomitant drop in S-phase in mouse colon cancer MC26 cells. We also showed that methylselenol inhibits colon cancer cell proliferation and tumor growth potential through the regulation of key p53 tumor suppressor gene pathway related cell cycle and apoptosis. These new data will be useful for scientists and health-care professionals who are interested in understanding the action of selenium as a nutrient and cancer prevention.
Technical Abstract: It is has been hypothesized that methylselenol is a critical selenium (Se) metabolite for anticancer activity in vivo. In this study, we used a protein array which contained 112 different antibodies known to be involved in p53 pathway to investigate the molecular targets of methylselenol in human HCT116 colon cancer cells. The array analysis indicated that methylselenol exposure changed the expression of 13 protein targets that directly related to the regulation of cell cycle and apoptosis. Subsequently, we confirmed these proteins with western blotting approach, and found that methylselenol increased the expression Bid, Caspase 6, GADD153 and p21 but reduced the level of cMyc, E2F1 and Phos p38. Consistent with our previous data, methylselenol also inhibited cell growth and led to an increase in G1 and G2 fractions with a concomitant drop in S-phase in mouse colon cancer MC26 cells. These methylselenol-treated MC26 cells had significant less tumor growth potential compared with that of untreated MC26 cells when these cells were transplanted to their immune-competent Balb/c mice. The inhibitory effect of methylselenol on tumor growth potential did not differ in those mice fed with either 10% or 45% fat diet. Taken together, methylselenol inhibits colon cancer cell proliferation and tumor growth potential through the regulation of key genes related cell cycle and apoptosis.