ReferenceID 2524
Oleanolic acid blocks the purine salvage pathway for cancer therapy by inactivating SOD1 and stimulating lysosomal proteolysis
Mol Ther Oncolytics
Metabolic reprogramming is a core hallmark of cancer and is key for tumorigenesis and tumor progression. Investigation of metabolic perturbation by anti-cancer compounds would allow a thorough understanding of the underl
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- Reference Id
- 2524
- Evidence Id
- 19114
- Core Evidence Id
- 19114
- Source Reference Id
- 5044
- Herb2 Reference Id
- HBREF005841
- Subject Paper Key
- HBIN037940_34703880
- Pubmed Id
- 34703880
- Doi
- 10.1016/j.omto.2021.08.013
- Paper Title
- Oleanolic acid blocks the purine salvage pathway for cancer therapy by inactivating SOD1 and stimulating lysosomal proteolysis
- Paper Abstract
- Metabolic reprogramming is a core hallmark of cancer and is key for tumorigenesis and tumor progression. Investigation of metabolic perturbation by anti-cancer compounds would allow a thorough understanding of the underlying mechanisms of these agents and identification of new anti-cancer targets. Here, we demonstrated that the administration of oleanolic acid (OA) rapidly altered cancer metabolism, particularly suppressing the purine salvage pathway (PSP). PSP restoration significantly opposed OA-induced DNA replication and cell proliferation arrest, underscoring the importance of this pathway for the anti-cancer activity of OA. Hypoxanthine-guanine phosphoribosyltransferase (HGPRT) and 5'-nucleotidase (5'-NT), two metabolic enzymes essential for PSP activity, were promptly degraded by OA via the lysosome pathway. Mechanistically, OA selectively targeted superoxide dismutase 1 (SOD1) and yielded reactive oxygen species (ROS) to activate the AMP-activated protein kinase (AMPK)/mammalian target of rapamycin complex 1 (mTORC1)/macroautophagy pathway, thus eliciting lysosomal degradation of HGPRT and 5'-NT. Furthermore, we found that the PSP was overactivated in human lung and breast cancers, with a negative correlation with patient survival. The results of this study elucidated a new anti-cancer mechanism of OA by restraining the PSP via the SOD1/ROS/AMPK/mTORC1/macroautophagy/lysosomal pathway. We also identified the PSP as a new target for cancer treatment and highlighted OA as a potential therapeutic agent for cancers with high PSP activity.
- Journal
- Mol Ther Oncolytics
- Publish Year
- 2021
- Experiment Subject
- human; patient
- Experiment Type
- Animal & Cell Experiment
- Phenotype Related
- Lung And Breast Cancers; Cancers; Tumor; Cancer
- Paper Title Cn
- Paper Title En
- Oleanolic acid blocks the purine salvage pathway for cancer therapy by inactivating SOD1 and stimulating lysosomal proteolysis
- Bilingual Status
- semi_complete