Methionine deprivation suppresses triple-negative breast cancer metastasisin vitroandin vivo

// Hyein Jeon 1, 2, * , Jae Hwan Kim 1, 2, * , Eunjung Lee 1, 2, 3, * , Young Jin Jang 1, 2,4 , Joe Eun Son 1, 2 , Jung Yeon Kwon 5 , Tae-gyu Lim 1, 2, 6 , Sunghoon Kim 7 , Jung Han Yoon Park 8 , Jong-Eun Kim 1, 2 , Ki Won Lee 1, 2 1 Major in Biomodulation, Department of Agricultural Biotechnology and Research Institute for Agriculture and Life Sciences, Seoul National University, Seoul, Republic of Korea 2 Advanced Institutes of Convergence Technology, Seoul National University, Suwon, Republic of Korea 3 Traditional Alcoholic Beverage Research Team, Korea Food Research Institute, Seongnam, Republic of Korea 4 Metabolic Mechanism Research Group, Korea Food Research Institute, Seongnam, Republic of Korea 5 Program in Molecular Medicine, University of Massachusetts Medical School, Worcester, MA, USA 6 Division of Strategic Food Research, Korea Food Research Institute, Seongnam, Republic of Korea 7 Medicinal Bioconvergence Research Center, College of Pharmacy, Seoul National University, Seoul, Republic of Korea 8 Department of Food Science and Nutrition, Hallym University, Chuncheon, Republic of Korea * These authors have contributed equally to this work Correspondence to: Jong-Eun Kim, email: idonlik1@snu.ac.kr Ki Won Lee, email: kiwon@snu.ac.kr Keywords: methionine, triple-negative breast cancer, metastasis, cancer therapy Received: March 25, 2016 Accepted: July 27, 2016 Published: August 25, 2016 ABSTRACT Nutrient deprivation strategies have been proposed as an adjuvant therapy for cancer cells due to their increased metabolic demand. We examined the specific inhibitory effects of amino acid deprivation on the metastatic phenotypes of the human triple-negative breast cancer (TNBC) cell lines MDA-MB-231 and Hs 578T, as well as the orthotopic 4T1 mouse TNBC tumor model. Among the 10 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, 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 in MDA-MB-231 cells. Furthermore, methionine restriction downregulated the metastasis-related factor urokinase plasminogen activatior and upregulated plasminogen activator inhibitor 1 mRNA expression. Animals on the methionine-deprived diet showed lower lung metastasis rates compared to mice on the control diet. Taken together, these results suggest that methionine restriction could provide a potential nutritional strategy for more effective cancer therapy.