Oleanolic acid blocks the purine salvage pathway for cancer therapy by inactivating SOD1 and stimulating lysosomal proteolysis
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. H...
| Main Authors: | , , , , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Elsevier
2021-12-01
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| Series: | Molecular Therapy: Oncolytics |
| Subjects: | |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S2372770521001248 |
| _version_ | 1819095344770711552 |
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| author | 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 |
| author_facet | 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 |
| author_sort | Dan Liu |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-12-21T23:41:49Z |
| format | Article |
| id | doaj.art-c84ed287fd68418eacb0ca80bdd3f843 |
| institution | Directory Open Access Journal |
| issn | 2372-7705 |
| language | English |
| last_indexed | 2024-12-21T23:41:49Z |
| publishDate | 2021-12-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Molecular Therapy: Oncolytics |
| spelling | doaj.art-c84ed287fd68418eacb0ca80bdd3f8432022-12-21T18:46:12ZengElsevierMolecular Therapy: Oncolytics2372-77052021-12-0123107123Oleanolic acid blocks the purine salvage pathway for cancer therapy by inactivating SOD1 and stimulating lysosomal proteolysisDan Liu0Xing Jin1Guanzhen Yu2Mingsong Wang3Lei Liu4Wenjuan Zhang5Jia Wu6Fengying Wang7Jing Yang8Qin Luo9Lili Cai10Xi Yang11Xisong Ke12Yi Qu13Zhenye Xu14Lijun Jia15Wen-Lian Chen16Cancer Institute, Longhua Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai 200032, ChinaCancer Institute, Longhua Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai 200032, ChinaCancer Institute, Longhua Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai 200032, ChinaDepartment of Thoracic Cardiovascular Surgery, Xinhua Hospital of Shanghai Jiaotong University School of Medicine, Shanghai 200092, ChinaDepartment of Thoracic Surgery, the Affiliated Tumor Hospital of Nantong University, Nantong 226361, ChinaCancer Institute, Fudan University Shanghai Cancer Center, Shanghai 200032, ChinaCancer Institute, Longhua Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai 200032, ChinaCancer Institute, Longhua Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai 200032, ChinaCancer Institute, Longhua Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai 200032, ChinaCancer Institute, Longhua Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai 200032, ChinaCancer Institute, Longhua Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai 200032, ChinaCancer Institute, Longhua Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai 200032, ChinaCenter for Chemical Biology, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, ChinaCenter for Chemical Biology, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, ChinaDepartment of Oncology, Longhua Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai 200032, ChinaCancer Institute, Longhua Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai 200032, China; Corresponding author: Professor Lijun Jia, PhD, Cancer institute, Longhua Hospital, Shanghai University of Traditional Chinese Medicine, Building 12 RM 601, No. 725 South Wanping Rd., Shanghai 200032, China.Cancer Institute, Longhua Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai 200032, China; Corresponding author: Wen-Lian Chen, PhD, Cancer Institute, Longhua Hospital, Shanghai University of Traditional Chinese Medicine, Building 12 RM 607, No. 725 South Wanping Rd., Shanghai 200032, China.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.http://www.sciencedirect.com/science/article/pii/S2372770521001248oleanolic acidpurine salvage pathwayhypoxanthine-guanine phosphoribosyltransferase5′-nucleotidasesuperoxide dismutase 1macroautophagy |
| spellingShingle | 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 Oleanolic acid blocks the purine salvage pathway for cancer therapy by inactivating SOD1 and stimulating lysosomal proteolysis Molecular Therapy: Oncolytics oleanolic acid purine salvage pathway hypoxanthine-guanine phosphoribosyltransferase 5′-nucleotidase superoxide dismutase 1 macroautophagy |
| title | Oleanolic acid blocks the purine salvage pathway for cancer therapy by inactivating SOD1 and stimulating lysosomal proteolysis |
| title_full | Oleanolic acid blocks the purine salvage pathway for cancer therapy by inactivating SOD1 and stimulating lysosomal proteolysis |
| title_fullStr | Oleanolic acid blocks the purine salvage pathway for cancer therapy by inactivating SOD1 and stimulating lysosomal proteolysis |
| title_full_unstemmed | Oleanolic acid blocks the purine salvage pathway for cancer therapy by inactivating SOD1 and stimulating lysosomal proteolysis |
| title_short | Oleanolic acid blocks the purine salvage pathway for cancer therapy by inactivating SOD1 and stimulating lysosomal proteolysis |
| title_sort | oleanolic acid blocks the purine salvage pathway for cancer therapy by inactivating sod1 and stimulating lysosomal proteolysis |
| topic | oleanolic acid purine salvage pathway hypoxanthine-guanine phosphoribosyltransferase 5′-nucleotidase superoxide dismutase 1 macroautophagy |
| url | http://www.sciencedirect.com/science/article/pii/S2372770521001248 |
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