c-Myc activates multiple metabolic networks to generate substrates for cell-cycle entry.

Area of Science:

• Cellular metabolism
• Molecular oncology
• Biochemistry

Background:

• Cell proliferation depends on coordinated cytosolic and mitochondrial metabolic pathways.
• The c-myc oncogene regulates metabolic pathway genes but its role in cell-cycle entry metabolism is unclear.

Purpose of the Study:

• To investigate the role of endogenous c-Myc in regulating metabolic networks during cell-cycle entry.
• To elucidate the metabolic fates of glucose in Myc-expressing versus non-expressing cells.

Main Methods:

• Utilized [U-(13)C] glucose tracing in serum-stimulated Myc(+/+) and Myc(-/-) fibroblasts.
• (13)C isotopomer NMR analysis to track metabolic fates.
• Assessed O-linked N-acetylglucosamine protein modification and hexosamine biosynthesis.

Main Results:

• Endogenous c-Myc increased (13)C labeling in ribose sugars, purines, and amino acids.
• Demonstrated increased pentose phosphate pathway and tricarboxylic acid cycle activity.
• Observed increased O-linked N-acetylglucosamine modification; hexosamine biosynthesis inhibition impaired Myc-driven proliferation.

Conclusions:

• Myc oncogene plays a central role in organizing metabolic networks in cycling cells.
• Myc directs glucose metabolism towards biosynthesis pathways essential for proliferation.
• Myc's function in metabolic regulation may explain its oncogenic role in human cancers.