Inhibition of Triple Negative Breast Cancer Metastasis by Methionine Restriction

Abstract

Nutrient deprivation strategies have been proposed as an adjuvant therapy for cancer cells due to their increased metabolic demand. Herein, I examined the specific inhibitory effects of amino acid deprivation on the metastatic phenotypes of the human TNBC lines MDA-MB231 and Hs 578T cells, as well as the orthotopic 4T1 mouse TNBC tumor model. Of the essential amino acids tested, methionine deprivation elicited the strongest inhibitory effects on the migration and invasion of these cancer cells. Methionine deprivation reduced the phosphorylation of focal adhesion kinase (FAK), as well as the activity and mRNA expression of matrix metalloproteinases MMP-2 and MMP-9, two major markers of metastasis, while increasing the mRNA expression of tissue inhibitor of metalloproteinase 1 (TIMP-1) in MDA-MB-231 cells. Furthermore, methionine restriction downregulated the metastasis-related factor urokinase plasminogen activatior (uPA) and upregulated plasminogen activator inhibitor 1 (PAI-1) mRNA expression. For the in vivo lung metastasis model, female BALB/c mouse were injected into the tail vein with 4T1 mouse TNBC cells and fed on a control diet, 0.1% methionine-containing diet, or a methionine-deprived diet. Animals on the methionine-deprived diet showed lower metastasis rates compared to mice on the control diet. Taken together, these results suggest that methionine deprivation has an inhibitory effect on the migration and invasion of TNBC cells, as well as lung metastasis in BALB/c mouse. Methionine restriction could therefore represent a potential nutritional strategy for more effective cancer therapy.