| Autor: |
Dan Liu, Xing Jin, Guanzhen Yu, Mingsong Wang, Lei Liu, Wenjuan Zhang, Jia Wu, Fengying Wang, Jing Yang, Qin Luo, Lili Cai, Xi Yang, Xisong Ke, Yi Qu, Zhenye Xu, Lijun Jia, Wen-Lian Chen |
| Jazyk: |
angličtina |
| Rok vydání: |
2021 |
| Předmět: |
|
| Zdroj: |
Molecular Therapy: Oncolytics, Vol 23, Iss , Pp 107-123 (2021) |
| Druh dokumentu: |
article |
| ISSN: |
2372-7705 |
| DOI: |
10.1016/j.omto.2021.08.013 |
| 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. |
| Databáze: |
Directory of Open Access Journals |
| Externí odkaz: |
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