Phosphatidylinositol 3-Kinase Mediates the Ability of Retinol to Decrease Colorectal Cancer Cell Invasion

Abstract

Previously, we showed that retinol (vitamin A) decreased both colorectal cancer cell invasion and phosphatidylinositol 3-kinase (PI3K) activity through a retinoic acid receptor–independent mechanism. Here, we determined if these phenomena were related by using parental HCT-116 cells that harbor 1 allele of wild-type PI3K and 1 allele of constitutively active (ca) PI3K and 2 mutant HCT-116 cell lines homozygous for caPI3K. In vitro, treatment of parental HCT-116 cells with 10 μM retinol reduced cell invasion whereas treatment of mutant HCT-116 cell lines with retinol did not. Treatment with 10 μM retinol also decreased the activity of matrixmetalloproteinase-9 and increased tissue inhibitor of matrixmetalloproteinase-I levels in parental, but not mutant, HCT-116 cells. Finally, parental or mutant cells were intrasplenically injected into athymic mice consuming diets with or without supplemental vitamin A. As expected, vitamin A supplementation tended (P = 0.18) to reduce the incidence of metastases in mice injected with the parental cell line and consuming the supplemented diet. In contrast, metastatic incidence was not affected (P = 1.00) by vitamin A supplementation in mice injected with mutant cells. These data indicate that the capacity of retinol to inhibit PI3K activity confers its ability to decrease colorectal cancer metastasis.

ACKNOWLEDGMENTS

The authors would like to thank Dr. Bert Vogelstein, M.D. of the Sidney Kimmel Comprehensive Cancer Center, Howard Hughes Medical Institute, and Johns Hopkins University Medical Institution, Baltimore, MD for donating the HCT-116 human colon cancer cell lines expressing 2 alleles of caPI3K. The authors thank Lindsay Appleby and Elizabeth Daniels for assistance with the animal work. We would also like to thank the Histology & Tissue Processing Facility Core in the University of Texas M.D. Anderson Cancer Center for immunohistochemical processing, and especially acknowledge Dr. Claudio Conti, D.V.M., for his assistance in analyzing the immunohistochemistry and assessing cirrhosis.

Additional information

Funding

The in vitro research described herein was supported by a grant from the National Institutes of Health to M.L. # 5 [R21 CA120414-02]. The in vivo research was supported by a grant from the American Institute for Cancer Research to M.L.