Glutamine deficiency in solid tumor cells confers resistance to ribosomal RNA synthesis inhibitors

Abstract

Ribosome biogenesis is an energetically expensive program that is dictated by nutrient availability. Here we report that nutrient deprivation severely impairs precursor ribosomal RNA (pre-rRNA) processing and leads to the accumulation of unprocessed rRNAs. Upon nutrient restoration, pre-rRNAs stored under starvation are processed into mature rRNAs that are utilized for ribosome biogenesis. Failure to accumulate pre-rRNAs under nutrient stress leads to perturbed ribosome assembly upon nutrient restoration and subsequent apoptosis via uL5/uL18-mediated activation of p53. Restoration of glutamine alone activates p53 by triggering uL5/uL18 translation. Induction of uL5/uL18 protein synthesis by glutamine is dependent on the translation factor eukaryotic elongation factor 2 (eEF2), which is in turn dependent on Raf/MEK/ERK signaling. Depriving cells of glutamine prevents the activation of p53 by rRNA synthesis inhibitors. Our data reveals a mechanism that tumor cells can exploit to suppress p53-mediated apoptosis during fluctuations in environmental nutrient availability.

Metabolic adaptations of cancer in extreme tumor microenvironments

“…Recently, it has been shown that under nutrient‐deprived conditions, the source of acetyl‐CoA is changed from citrate to acetate in cancer cells by the enzyme ACSS2, which produces acetyl‐CoA from acetate 34–37 (Figure 2). We also reported that glutamine deprivation makes cancer cells resistant to the RNA polymerase I inhibitor through an impaired p53 activation pathway 13 . Furthermore, it has been shown that SREBP2 , a regulator of cholesterol metabolism, is activated in acidic pH environments, which also induces metabolic shifts 14 .…”

“…We have previously investigated multilayered analyses in hypoxia and nutrient starvation and reported that hypoxia, nutrient starvation, and acidic pH had distinct genetic, epigenetic, and metabolic regulations. 8,13,14 Other tumor microenvironmental stress is known as ER stress.…”

“…In addition, HIF is known to induce the expression of genes related to metastasis and invasion, and the hypoxic adaptation response is thought to contribute significantly to the metabolic adaptations of cancer cells 11,12 (Figure 1). We have previously investigated multilayered analyses in hypoxia and nutrient starvation and reported that hypoxia, nutrient starvation, and acidic pH had distinct genetic, epigenetic, and metabolic regulations 8,13,14 …”

“…We also reported that glutamine deprivation makes cancer cells resistant to the RNA polymerase I inhibitor through an impaired p53 activation pathway. 13 Furthermore, it has been shown that SREBP2 , a regulator of cholesterol metabolism, is activated in acidic pH environments, which also induces metabolic shifts. 14 These findings suggest that cancer cells maintain proliferation by skillfully shifting metabolic pathways under adverse conditions, such as hypoxia, nutrient starvation, and acidic pH.…”

Targeting the cell and non-cell autonomous regulation of 47S synthesis by GCN2 in colon cancer

“…Our results show that GCN2 also supports RiBi reprogramming. The adaptive cellular response to starvation implicates limitation of both RNA Pol I activity and rRNA processing (Pan et al, 2022). Our data supports a model in which GCN2 preserves the repression of 47S expression in amino acid-depleted conditions likely to sustain the translational dedifferentiation program.…”