Cell Death of Prostate Cancer Cells by Specific Amino Acid Restriction Depends on Alterations of Glucose Metabolism

Selective amino acid restriction targets mitochondria resulting in DU145 and PC3 prostate cancer cell death. This study shows that restriction of tyrosine and phenylalanine (Tyr/Phe), glutamine (Gin), or methionine (Met) differentially modulates glucose metabolism, glycogen synthase kinase 3 beta (GSK3 beta), p53, and pyruvate dehydrogenase (PDH) in these two cell lines. In DU145 cells, Gin and Met restriction increase glucose consumption, but Tyr/Phe restriction does not. Addition of glucose to culture media diminishes cell death induced by Tyr/Phe-restriction. Addition of pyruvate reduces cell death due to Tyr/Phe and Gln restriction. Tyr/Phe, Gln and Met restriction increase phosphorylation of GSK3 beta-Ser(9), phosphorylation of p53-Ser(15) and reduce the mitochondrial localization of PDH. Addition of glucose or pyruvate to cultures significantly reverses the alterations in GSK3 beta, p53 and PDH induced by amino acid restriction. In p53-null PC3 cells, Tyr/Phe, Gln and Met restriction decreases glucose consumption, reduces phosphorylation of Akt-Ser(473), and increases phosphorylation of GSK3 beta-Ser(9). Addition of pyruvate or glucose reduces death of Met-restricted cells. Addition of glucose increases phosphorylation of Akt-Ser473 in amino acid-restricted cells reduces phosphorylation of GSK3 beta-Ser(9) in Tyr/Phe and Gin restricted cells and increases phosphorylation of GSK3 beta-Ser(9) in Met restricted cells. Addition of pyruvate reduces phosphorylation of GSK3 beta-Ser(9) in all amino acid-restricted cells. In summary, cell death induced by specific amino acid restriction is dependent on or closely related to the modulation of glucose metabolism. GSK3 beta (DU145 and PC3) and p53 (DU145) are crucial switches connecting metabolism and these signaling molecules to cell survival during amino acid restriction. J. Cell. Physiol. 224: 491-500, 2010. (C) 2010 Wiley-Liss, Inc.