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Copyright by Eunyoung Park 2007 - The University of Texas at Austin

Copyright by Eunyoung Park 2007 - The University of Texas at Austin

However, we did not

However, we did not observe MMP-2 and -9 staining in the metastatic liver tumors in the current study. These tumors were derived from the same cell line, HCT-116, used our in vitro study. We hypothesized that the effect of vitamin A on the activity of these proteins may be dependent upon stage of metastasis. For example, MMP-2 and -9 may required at the beginning of liver metastases. Therefore, mice may need to be sacrificed at an earlier time point to determine changes in MMP-2 and -9 protein levels in response to dietary vitamin A supplementation. We detected phospho-Akt staining in liver metastases of human colon cancer cells, however, the level of phospho-Akt was not changed by vitamin A supplementation. Rychahou et al showed that inhibition of PI3K subunits, either p85 or p110, using siRNA decreased tumor multiplicity (176). In the Rychahou et al study, they also examined the expression of Akt1 and Akt 2. In human, there are three isoforms of Akt, designated Akt1, 2, and 3. Previous studies showed increased Akt 1 and 2 activation in colorectal cancers and colon cancer cell lines (183,184). The Rychahou et al study showed Akt1 expression was highly variable but increased expression of Akt 2 was found in all human colorectal cancers especially in the late stage of cancers. Samuels et al showed that Akt1 is the predominant form of Akt in HCT-116 cells (185). However, Bruzek et al showed expression of both Akt 1 and 2 in the same cell line (186). Akt3 expression has not been studied in this cell line. The contribution of Akt1 and Akt2 to cell invasion is currently unclear in the HCT-116 cell line. Both total and phospho-Akt antibody used in this study detect all three types of Akt. Therefore, we might not detect the changes of activation of the specific isoform of Akt which is important for liver metastasis of colon 109

cancer. Therefore, determination of the Akt isoform required for invasion should occur before additional investigation of PI3K activity in liver metastasis. In conclusion, the present study shows that dietary vitamin A supplementation decreases tumor incidence in mice subjected to a chemotherapy dietary regimen and tumor multiplicity in mice subjected to chemoprevention regimen. However, the inhibition of MMP-2, -9 and PI3K activity by retinol treatment showed in our previous in vitro studies was not observed here. To our knowledge, this study is the first to show that dietary vitamin A supplementation inhibits colon cancer metastasis to the liver in a mouse model. Taken together, these data suggest the possibility of dietary vitamin A supplementation for colon cancer therapy and prevention. ACKNOWLEDGEMENT This research was supported by NIH grant #1R21CA120414-01A1 and NIEHS Center Grant ES 07784. The authors thank Erik Wilder, Kally O'Reilly and Louis Doan for helping with the mice surgery, Dr. Susan Fischer, Dr. Kaoru Kiguchi, and Shanna Maika for training. We also thank the Histology & Tissue Processing Facility Core in the University of Texas M.D. Anderson Cancer Center for immunohistochemical processing. 110

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