The Effect of Leucine Restriction on Akt/mTOR Signaling in Breast Cancer Cell Lines In Vitro and In Vivo

Abstract

The mammalian target of rapamycin (mTOR) is a central controller of cell growth and is currently being investigated as a potential target in breast cancer therapy. The essential amino acid leucine has been proposed to regulate mTOR signaling. The objective of this study was to determine whether leucine restriction would inhibit mTOR signaling in breast cancer cells. Leucine restriction did not decrease mTOR signaling in any of the 8 breast cancer cell lines tested. In addition, in vivo administration of a leucine-free diet for up to 4 days did not result in a decrease in phosphorylation of mTOR target proteins in breast cancer xenografts. Further, in 3 different cell lines, an increase in Akt phosphorylation was observed after leucine restriction. This was observed without a decrease in S6K phosphorylation, suggesting a mechanism different from the feedback loop activation of Akt observed with rapamycin treatment. We conclude that leucine restriction is not sufficient to inhibit mTOR signaling in most breast cancer cell lines but is associated with activation of survival molecule Akt, making leucine deprivation an undesirable approach for breast cancer therapy.

ACKNOWLEDGMENTS

This study was supported by grants from NIH1 R01 CA112199 and American Institute of Cancer Research (to F. M.-B.), NIH 5 T32 CA09599 (F. M.-B.; D. L.), and the U. T. M.D. Anderson Cancer Center Support Core Grant (CA 16672). We thank Judy Roehm for assistance with manuscript preparation.