Oleanolic acid blocks the purine salvage pathway for cancer therapy by inactivating SOD1 and stimulating lysosomal proteolysis
| Autor: | Lijun Jia, Zhenye Xu, Fengying Wang, Guanzhen Yu, Jia Wu, Xing Jin, Lei Liu, Qin Luo, Xi Yang, Mingsong Wang, Wenlian Chen, Xisong Ke, Wenjuan Zhang, Dan Liu, Yi Qu, Lili Cai, Jing Yang |
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| Rok vydání: | 2021 |
| Předmět: |
Cancer Research
mTORC1 medicine.disease_cause superoxide dismutase 1 oleanolic acid Lysosome medicine Pharmacology (medical) Protein kinase A purine salvage pathway RC254-282 Chemistry Autophagy Neoplasms. Tumors. Oncology. Including cancer and carcinogens Cancer AMPK medicine.disease eye diseases hypoxanthine-guanine phosphoribosyltransferase macroautophagy lysosomal degradation medicine.anatomical_structure Oncology Hypoxanthine-guanine phosphoribosyltransferase Cancer research Molecular Medicine Original Article 5′-nucleotidase Carcinogenesis |
| Zdroj: | Molecular Therapy: Oncolytics, Vol 23, Iss, Pp 107-123 (2021) Molecular Therapy Oncolytics |
| ISSN: | 2372-7705 |
| Popis: | 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. Graphical abstract Mechanistic study of natural compounds with anti-cancer activity would identify new targets for cancer treatment. Here we found that the purine salvage pathway (PSP) was a crucial target of oleanolic acid (OA) for cancer therapy. Moreover, OA suppressed PSP of cancer cells via activating the SOD1/ROS/AMPK/mTORC1/macroautophagy/lysosomal pathway. |
| Databáze: | OpenAIRE |
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