MYC-Dependent rRNA Catabolism Stress Dictates Survival Heterogeneity of Hepatocellular Carcinoma Cells Under Glutamine Deprivation

Abstract

Tumor cells commonly exhibit a preferential uptake of glutamine to support the heightened metabolic demands. However, the therapeutic potential of targeting glutamine metabolism is severely limited by the heterogeneous responses of cancer cells to glutamine deprivation. In this study, we identified a ribophagy-adenosine-MYC positive feedback loop that was activated and determined cell fate under glutamine deprivation. In sensitive cells, highly expressed MYC acted as a scaffold to recruit Unc-51 like autophagy activating kinase 1, which phosphorylated ribosomal protein L12 to initiate ribophagy. This process drove extensive rRNA catabolism and a burst of reactive oxygen species, ultimately leading to cell death. Moreover, adenosine generated during this cascade enhanced MYC expression via its 3'-UTR region, locking the loop into a self-reinforcing hyperactivated state. In contrast, tolerant cells exhibited lower MYC expression, which constrained the loop to a low-activity and subcritical steady state, thereby enabling survival under glutamine deprivation. Consequently, MYC-high tumors were vulnerable to glutaminase inhibition alone (CB-839), while MYC-low tumors required combination therapy with CB-839 and a pro-oxidant (elesclomol) to achieve tumor eradication. This study establishes MYC expression as a key determinant of sensitivity to glutamine deprivation, reveals the central role of ribophagy within the glutamine deprivation-triggered positive feedback loop, and uncovers a non-canonical, scaffold-like function of MYC in rRNA catabolism. These findings highlight a potential combination strategy to overcome a major bottleneck in targeting glutamine metabolism.