Oleanolic acid blocks the purine salvage pathway for cancer therapy by inactivating SOD1 and stimulating lysosomal proteolysis

• Published in: Molecular therapy. Oncolytics 2021-12, Vol.23, p.107-123
• Main Authors: Liu, Dan, Jin, Xing, Yu, Guanzhen, Wang, Mingsong, Liu, Lei, Zhang, Wenjuan, Wu, Jia, Wang, Fengying, Yang, Jing, Luo, Qin, Cai, Lili, Yang, Xi, Ke, Xisong, Qu, Yi, Xu, Zhenye, Jia, Lijun, Chen, Wen-Lian
• Format: Article
• Language: English
• Subjects: 5′-nucleotidase; hypoxanthine-guanine phosphoribosyltransferase; lysosomal degradation; macroautophagy; oleanolic acid; Original; purine salvage pathway; superoxide dismutase 1
• ISSN: 2372-7705; 2372-7705
• DOI: 10.1016/j.omto.2021.08.013

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. [Display omitted] 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.