期刊
出版社
NATL ACAD SCIENCES
DOI: 10.1073/pnas.2018229118
关键词
proteasome; myeloma; proteostasis; GCN2; metabolism
资金
- Amgen research grant
- Cancer Research UK Advanced Clinician Scientist Fellowship [C41494, A29035]
- Cancer Research UK Small Molecule Drug Discovery Award by the Stand Up To Cancer (SU2C) campaign for Cancer Research UK, a The Blood Fund Imperial Health Charity research grant [C41494, A27988]
- Hugh and Josseline Langmuir Centre for Myeloma Research at Imperial College London
- Cancer Research UK Imperial Centre at Imperial College London [C17375, A19482]
- Imperial Experimental Cancer Medicine Centre
- NIHR BRC
- NIHR Imperial BRC Institute for Translational Medicine andTherapeutics (ITMAT) Push for Impact grant [RDF01]
- NIHR BRC based at Imperial College Healthcare NHS Trust and Imperial College London
The study reveals the complex mechanisms of proteotoxic stress resolution in cancer cells recovering from chemotherapy-induced stress, involving extensive changes across the transcriptome, proteome, and metabolome, as well as dynamic alterations in glucose and lipid metabolism and suppression of mitochondrial function. Additionally, recovering cells are more vulnerable to specific insults, with a key vulnerability associated with cellular response to amino acid scarcity.
Cancer cells can survive chemotherapy-induced stress, but how they recover from it is not known. Using a temporal multiomics approach, we delineate the global mechanisms of proteotoxic stress resolution in multiple myeloma cells recovering from proteasome inhibition. Our observations define layered and protracted programs for stress resolution that encompass extensive changes across the transcriptome, proteome, and metabolome. Cellular recovery from proteasome inhibition involved protracted and dynamic changes of glucose and lipid metabolism and suppression of mitochondrial function. We demonstrate that recovering cells are more vulnerable to specific insults than acutely stressed cells and identify the general control nonderepressable 2 (GCN2)-driven cellular response to amino acid scarcity as a key recovery-associated vulnerability. Using a transcriptome analysis pipeline, we further show that GCN2 is also a stress-independent bona fide target in transcriptional signaturedefined subsets of solid cancers that share molecular characteristics. Thus, identifying cellular trade-offs tied to the resolution of chemotherapy-induced stress in tumor cells may reveal new therapeutic targets and routes for cancer therapy optimization.
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