TYROSINE AND PHENYLALANINE RESTRICTION INDUCES G0 G1 CELL-CYCLE ARREST IN MURINE MELANOMA IN-VITRO AND IN-VIVO/

Tyr-Phe and Met limitation in vitro inhibited cell proliferation and p roliferating cell nuclear antigen (PCNA) expression to a gl eater exte nt than serum limitation. Tyr-Phe and serum limitation arrested cells in the G0/GI phase; Met limitation blocked cells in the G0/GI and S ph ases. Tyr-Phe limitation progressively decreased cyclin D-1 expression to 30% of control within four days and did not affect expression of c yclin D-3 or cyclin-dependent kinase (CDK2, CDK4, and CDK5) expression . Met limitation decreased cyclin D-3 expression to 25% of control and CDK2 expression to 32% of control by Day 4 and did not affect express ion of cyclin D-1, CDK4, and CDK5. Serum limitation inhibited cyclin D -1 and cyclin D-3 expression to 24% of control after four days and did not effect CDK expression. Expression of two CDK inhibitors, p21(WAF1 /Cip1) and P27(Kip1), was not changed by amino acid or serum limitatio n. Dietary restriction of Tyr-Phe in mice bearing subcutaneous B16BL6 melanoma tumors decreased tumor growth rate compared with mice fed a n ormal diet. Tumors from Tyr-Phe-restricted mice exhibited decreased PC NA expression, G0/GI phase cell cycle arrest and reduced cyclin D-1 ex pression. These data indicate that decreased tumor growth in vivo asso ciated with dietary restriction of Tyr and Phe is cell cycle specific.