Specific Amino Acid Dependency Regulates Invasiveness and Viability of Androgen-Independent Prostate Cancer Cells

Abstract

Androgen-independent prostate cancer is resistant to therapy and is often metastatic. Here we studied the effect of deprivation of tyrosine and phenylalanine (Tyr/Phe), glutamine (Gln), or methionine (Met), in vitro on human DU145 and PC3 androgen-independent prostate cancer cells, and on nontumorigenic human infant foreskin fibroblasts and human prostate epithelial cells. Deprivation of the amino acids similarly inhibited growth of DU145 and PC3 cells, arresting the cell cycle at G0/G1. Met and Tyr/Phe deprivation induces apoptosis in DU145, but only Met deprivation induces apoptosis in PC3 cells. The growth of normal cells is inhibited, but no apoptosis is induced by amino acid deprivation. Tyr/Phe deprivation inhibits expression and phosphorylation of focal adhesion kinase (FAK) and extracellular-regulated kinase (ERK) in DU145 but not PC3 or normal cells. Met deprivation inhibits phosphorylation but not protein expression of FAK and ERK in PC3. Therefore, apoptosis of DU145 and PC3 cells by amino acid restriction is FAK and ERK dependent. Tyr/Phe and Met deprivation inhibits invasion of DU145 and PC3, but Gln deprivation only inhibits invasion of DU145 cells. This indicates that the inhibition of invasion is not dependent on induction of apoptosis. The inhibition of invasion by Tyr/Phe restriction in DU145 and Met restriction in PC3 is consistent with the inhibition on FAK/ERK signaling. The inhibition of Tyr/Phe restriction in PC3 and Gln restriction in DU145 is not associated with inhibition of FAK/ERK. This indicates that FAK/ERK-dependent and independent pathways are modulated by specific amino acid restriction. This study shows the potential for specific amino acid restriction to treat prostate cancer.

Selective amino acid restriction targets mitochondria to induce apoptosis of androgen‐independent prostate cancer cells

“…In prostate cancer cell lines, restriction of tyrosine and phenylalanine (Tyr/Phe) or methionine (Met) induces apoptosis of DU145 cells, but only Met restriction induces apoptosis of PC3 cells. However, neither of the restrictions induces apoptosis of normal prostate epithelial cells (Fu et al, 2003). We found that apoptosis induced by specific amino acid restriction is a relatively slow process (Fu et al, , 2003Ballif and Blenis, 2001;Ge et al, 2002).…”

“…However, neither of the restrictions induces apoptosis of normal prostate epithelial cells (Fu et al, 2003). We found that apoptosis induced by specific amino acid restriction is a relatively slow process (Fu et al, , 2003Ballif and Blenis, 2001;Ge et al, 2002). Raf and Akt are major survival pathways in mammalian cells; inhibition of these pathways results in slow cell death (Ballif and Blenis, 2001;Green and Evans, 2002).…”

“…FAK and PI3K also regulate the proapoptotic function of Bax, a Bcl-2 family protein (Gilmore et al, 2000). Phosphorylation of FAK is inhibited by specific amino acid restriction in cancer cells (Fu et al, , 2003.…”

Methionine Restriction and Modification of Epithelial Tight Junction Barrier Function and Permeability

“…Studies using murine or human melanoma cells showed that MR suppresses attachment and motility of melanoma cells by the inhibition of specific integrin expression, in turn through integrin-mediated focal adhesion kinase (FAK) phosphorylation [6]. In prostate cancer cells, MR not only induced apoptosis, but also reduced the invasiveness of two different prostate cell lines [16]. This effect seemed to be via a FAK/extracellular-regulated kinase (ERK)-dependent pathway [16] and Raf/Akt survival pathway [17].…”

“…In prostate cancer cells, MR not only induced apoptosis, but also reduced the invasiveness of two different prostate cell lines [16]. This effect seemed to be via a FAK/extracellular-regulated kinase (ERK)-dependent pathway [16] and Raf/Akt survival pathway [17]. MR also modulates g-protein activity and the relative abundance and phosphorylation of the motility proteins cofilin and profilin [14].…”