Asparagine sustains cellular proliferation and c-Myc expression in glutamine-starved cancer cells

During tumorigenesis, oncogene activation and metabolism rewiring are interconnected. Activated c-Myc upregulates several genes involved in glutamine metabolism, making cancer cells dependent on high levels of this amino acid to survive and proliferate. After studying the response to glutamine deprivation in cancer cells, it was found that gluta- mine starvation not only blocked cellular proliferation, but also altered c-Myc protein expression, leading to a reduction in the levels of the canonical c-Myc isoform and an increase in the expression of c-Myc 1, a c-Myc isoform translated from an in-frame 5' CUG codon. In an attempt to identify nutrients able to counteract glutamine deprivation effects, it was shown that, in the absence of glutamine, asparagine permitted cell survival and proliferation, and maintained c-Myc expression as in glutamine-fed cells, with high levels of canonical c-Myc and c-Myc 1 almost undetectable. In asparagine-fed cells, global protein translation was higher than in glutamine-starved cells, and there was an increase in the levels of glutamine synthe- tase (GS), whose activity was essential for cellular viability and proliferation. In glutamine-starved asparagine-fed cells, the inhibition of c-Myc activity led to a decrease in global protein translation and GS synthesis, suggesting an association between c-Myc expression, GS levels and cellular proliferation, mediated by asparagine when exogenous glutamine is absent.