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 greater extent than serum limitation. Tyr-Phe and serum limitation arrested cells in the G0/G1 phase; Met limitation blocked cells in the G0/G1 and S phases. Tyr-Phe limitation progressively decreased cyclin D1 expression to 30% of control within four days and did not affect expression of cyclin D3 or cyclin-dependent kinase (CDK2, CDK4, and CDK5) expression, Met limitation decreased cyclin D3 expression to 25% of control and CDK2 expression to 32% of control by Day 4 and did not affect expression of cyclin D1, CDK4, and CDK5. Serum limitation inhibited cyclin D1 and cyclin D3 expression to 24% of control after four days and did not effect CDK expression. Expression of two CDK inhibitors, p21WAF1/Cip1 and p27Kip1, 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/G1 phase cell cycle arrest, and reduced cyclin D1 expression. These data indicate that decreased tumor growth in vivo associated with dietary restriction of Tyr and Phe is cell cycle specific.
Fu
Y M
YM
Department of Pharmaceutical Sciences, College of Pharmacy, Washington State University, Pullman 99164-6510, USA.
Yu
Z X
ZX
Ferrans
V J
VJ
Meadows
G G
GG
D000818:Animals; D000911:Antibodies, Monoclonal / Q000276:immunology; D015153:Blotting, Western; D002453:Cell Cycle / Q000502:physiology*; D003470:Culture Media; D016213:Cyclins / Q000032:analysis / Q000096:biosynthesis; D004032:Diet; D005260:Female; D005434:Flow Cytometry; D007106:Immune Sera / Q000276:immunology; D008546:Melanoma, Experimental / Q000737:chemistry / Q000378:metabolism / Q000473:pathology*; D008715:Methionine / Q000378:metabolism; D051379:Mice; D010649:Phenylalanine / Q000172:deficiency / Q000378:metabolism*; D018809:Proliferating Cell Nuclear Antigen / Q000032:analysis / Q000096:biosynthesis; D011817:Rabbits; D051381:Rats; D013047:Specific Pathogen-Free Organisms; D013997:Time Factors; D014407:Tumor Cells, Cultured; D014443:Tyrosine / Q000172:deficiency / Q000378:metabolism*
D000911:Antibodies, Monoclonal; D003470:Culture Media; D016213:Cyclins; D007106:Immune Sera; D018809:Proliferating Cell Nuclear Antigen; D014443:Tyrosine; D010649:Phenylalanine; D008715:Methionine