Cell death of prostate cancer cells by specific amino acid restriction depends on alterations of glucose metabolism

Abstract

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 (Gln), or methionine (Met) differentially modulates glucose metabolism, glycogen synthase kinase 3beta (GSK3beta), p53, and pyruvate dehydrogenase (PDH) in these two cell lines. In DU145 cells, Gln 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 GSK3beta-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 GSK3beta, 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 GSK3beta-Ser(9). Addition of pyruvate or glucose reduces death of Met-restricted cells. Addition of glucose increases phosphorylation of Akt-Ser(473) in amino acid-restricted cells reduces phosphorylation of GSK3beta-Ser(9) in Tyr/Phe and Gln restricted cells and increases phosphorylation of GSK3beta-Ser(9) in Met restricted cells. Addition of pyruvate reduces phosphorylation of GSK3beta-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. GSK3beta (DU145 and PC3) and p53 (DU145) are crucial switches connecting metabolism and these signaling molecules to cell survival during amino acid restriction.

The Key Roles of GSK-3β in Regulating Mitochondrial Activity

“…Activated TPKI/GSK-3β is shown to phosphorylate and suppress PDH, leading to disruption of glucose metabolism [46]. Similar results are obtained in DU145 and PC3 cells [47]. Cardiolipin is an important mitochondrial phospholipid, which is essential for the electron transport chain and ATP production.…”

Differential effects of specific amino acid restriction on glucose metabolism, reduction/oxidation status and mitochondrial damage in DU145 and PC3 prostate cancer cells

“…These studies showed that selective amino acid restriction promotes mitochondrial outer membrane permeabilization and reduces intracellular ATP in DU145 and PC3 prostate cancer cells (5). Results of the present study showed that specific amino acid restriction differentially modulates cellular metabolism in the two cell lines (15), including glucose metabolism, cellular redox status and antioxidant systems. The increased glycolytic activity (Warburg effect) of cancer cells enhances the proliferation and resistance of the cells to apoptosis (16).…”

“…The increased glycolytic activity (Warburg effect) of cancer cells enhances the proliferation and resistance of the cells to apoptosis (16). We previously found that the addition of glucose or pyruvate differentially reduces or postpones the apoptotic effect of specific amino acid restriction in DU145 and PC3 cells (15). …”

Prioritizing Candidate Disease Metabolites Based on Global Functional Relationships between Metabolites in the Context of Metabolic Pathways

“…We found that 6 candidates were ranked in top 10 in both networks (Table 3). These top ranked metabolites were all reported to associate with initialization and development of prostate cancer [38]–[54]. For example, PROFANCY ranked the sorbitol at the first place.…”