Mitoribosomal synthetic lethality overcomes multidrug resistance in MYC-driven neuroblastoma
| Authors | |
|---|---|
| Year of publication | 2023 |
| Type | Article in Periodical |
| Magazine / Source | Cell Death and Disease |
| MU Faculty or unit | |
| Citation | |
| Web | https://www.nature.com/articles/s41419-023-06278-x |
| Doi | http://dx.doi.org/10.1038/s41419-023-06278-x |
| Keywords | ABDOMINAL AORTIC-ANEURYSMS; N-MYC; MITOCHONDRIAL TRANSLATION; DRUG-RESISTANCE; PROTEIN; DOXYCYCLINE; PHOSPHORYLATION; DEGRADATION; ACTIVATION; EXPRESSION |
| Attached files | |
| Description | Mitochondria are central for cancer responses to therapy-induced stress signals. Refractory tumors often show attenuated sensitivity to apoptotic signaling, yet clinically relevant molecular actors to target mitochondria-mediated resistance remain elusive. Here, we show that MYC-driven neuroblastoma cells rely on intact mitochondrial ribosome (mitoribosome) processivity and undergo cell death following pharmacological inhibition of mitochondrial translation, regardless of their multidrug/mitochondrial resistance and stem-like phenotypes. Mechanistically, inhibiting mitoribosomes induced the mitochondrial stress-activated integrated stress response (ISR), leading to downregulation of c-MYC/N-MYC proteins prior to neuroblastoma cell death, which could be both rescued by the ISR inhibitor ISRIB. The ISR blocks global protein synthesis and shifted the c-MYC/N-MYC turnover toward proteasomal degradation. Comparing models of various neuroectodermal tumors and normal fibroblasts revealed overexpression of MYC proteins phosphorylated at the degradation-promoting site T58 as a factor that predetermines vulnerability of MYC-driven neuroblastoma to mitoribosome inhibition. Reducing N-MYC levels in a neuroblastoma model with tunable MYCN expression mitigated cell death induction upon inhibition of mitochondrial translation and functionally validated the propensity of neuroblastoma cells for MYC-dependent cell death in response to the mitochondrial ISR. Notably, neuroblastoma cells failed to develop significant resistance to the mitoribosomal inhibitor doxycycline over a long-term repeated (pulsed) selection. Collectively, we identify mitochondrial translation machinery as a novel synthetic lethality target for multidrug-resistant MYC-driven tumors. |
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