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 proliferating cell nuclear antigen (PCNA) expression to a gl eater extent 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 phases. Tyr-Phe limitation progressively decreased cyclin D-1 expression to 30% of control within four days and did not affect expression of cyclin 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 expression 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 limitation. Dietary restriction of Tyr-Phe in mice bearing subcutaneous B16BL6 melanoma tumors decreased tumor growth rate compared with mice fed a normal diet. Tumors from Tyr-Phe-restricted mice exhibited decreased PCNA expression, G0/GI phase cell cycle arrest and reduced cyclin D-1 expression. These data indicate that decreased tumor growth in vivo associated with dietary restriction of Tyr and Phe is cell cycle specific.