A novel P38α MAPK activator Bruceine A exhibits potent anti-pancreatic cancer activity
Pancreatic cancer remains one of the cancers with the poorest prognosis bearing an overall 5-year survival rate of about 5%. Efficient new chemotherapic drugs are still highly desired. Here, bruceine A, a quassinoid identified from the dried fruits of Brucea javanica (L.) Merr., displayed the most p...
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| Format: | Article |
| Language: | English |
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Elsevier
2021-01-01
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| Series: | Computational and Structural Biotechnology Journal |
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| Online Access: | http://www.sciencedirect.com/science/article/pii/S200103702100249X |
| _version_ | 1818871978893770752 |
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| author | Cai Lu Lu Fan Peng-Fei Zhang Wei-Wei Tao Cheng-Bin Yang Er-Xin Shang Fei-Yan Chen Chun-Tao Che Hai-Bo Cheng Jin-Ao Duan Ming Zhao |
| author_facet | Cai Lu Lu Fan Peng-Fei Zhang Wei-Wei Tao Cheng-Bin Yang Er-Xin Shang Fei-Yan Chen Chun-Tao Che Hai-Bo Cheng Jin-Ao Duan Ming Zhao |
| author_sort | Cai Lu |
| collection | DOAJ |
| description | Pancreatic cancer remains one of the cancers with the poorest prognosis bearing an overall 5-year survival rate of about 5%. Efficient new chemotherapic drugs are still highly desired. Here, bruceine A, a quassinoid identified from the dried fruits of Brucea javanica (L.) Merr., displayed the most potent anti-proliferation activity against pancreatic cancer in vitro and in vivo. Phosphoproteomic analysis revealed p38α MAPK phosphorylation was involved in bruceine A’s action in MIA PaCa-2 cells. Utilizing fortebio octet system and microscale thermophoresis, we found p38α MAPK had high affinity for bruceine A. Molecular docking and molecular dynamic simulations showed that bruceine A widely bound to residues (Leu171, Ala172, Met179, Thr180, Val183) in P-loop of p38α MAPK. Key determinants of bruceine A binding with P-loop of p38α MAPK were 19-CO, 22-CH3, 32-CH3, and 34-CH3. Taken together, our findings demonstrate that bruceine A binds directly to p38α MAPK, which can be used to probe the role of p38α MAPK phosphorylation in pancreatic cancer progression, and as a novel lead compound for pancreatic cancer therapy. |
| first_indexed | 2024-12-19T12:31:31Z |
| format | Article |
| id | doaj.art-db339e8cfa7d40d4969b76e059451cca |
| institution | Directory Open Access Journal |
| issn | 2001-0370 |
| language | English |
| last_indexed | 2024-12-19T12:31:31Z |
| publishDate | 2021-01-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Computational and Structural Biotechnology Journal |
| spelling | doaj.art-db339e8cfa7d40d4969b76e059451cca2022-12-21T20:21:23ZengElsevierComputational and Structural Biotechnology Journal2001-03702021-01-011934373450A novel P38α MAPK activator Bruceine A exhibits potent anti-pancreatic cancer activityCai Lu0Lu Fan1Peng-Fei Zhang2Wei-Wei Tao3Cheng-Bin Yang4Er-Xin Shang5Fei-Yan Chen6Chun-Tao Che7Hai-Bo Cheng8Jin-Ao Duan9Ming Zhao10Jiangsu Collaborative Innovation Center of Chinese Medicinal Resources Industrialization, National and Local Collaborative Engineering Center of Chinese Medicinal Resources Industrialization and Formulae Innovative Medicine, Nanjing University of Chinese Medicine, Nanjing 210023, ChinaSchool of Medicine & Holistic Integrative Medicine, Nanjing University of Chinese Medicine, Nanjing 210023, ChinaJiangsu Collaborative Innovation Center of Chinese Medicinal Resources Industrialization, National and Local Collaborative Engineering Center of Chinese Medicinal Resources Industrialization and Formulae Innovative Medicine, Nanjing University of Chinese Medicine, Nanjing 210023, ChinaSchool of Chinese Medicine & School of Integrated Chinese and Western Medicine, Nanjing University of Chinese Medicine, Nanjing 210023, ChinaJiangsu Collaborative Innovation Center of Chinese Medicinal Resources Industrialization, National and Local Collaborative Engineering Center of Chinese Medicinal Resources Industrialization and Formulae Innovative Medicine, Nanjing University of Chinese Medicine, Nanjing 210023, ChinaJiangsu Collaborative Innovation Center of Chinese Medicinal Resources Industrialization, National and Local Collaborative Engineering Center of Chinese Medicinal Resources Industrialization and Formulae Innovative Medicine, Nanjing University of Chinese Medicine, Nanjing 210023, ChinaSchool of Chinese Medicine & School of Integrated Chinese and Western Medicine, Nanjing University of Chinese Medicine, Nanjing 210023, ChinaDepartment of Pharmaceutical Sciences, College of Pharmacy, University of Illinois at Chicago, Chicago, IL 60612, USACollaborative Innovation Center of Jiangsu Province of Cancer Prevention and Treatment of Chinese Medicine, Nanjing 210023, ChinaJiangsu Collaborative Innovation Center of Chinese Medicinal Resources Industrialization, National and Local Collaborative Engineering Center of Chinese Medicinal Resources Industrialization and Formulae Innovative Medicine, Nanjing University of Chinese Medicine, Nanjing 210023, China; Corresponding authors.Jiangsu Collaborative Innovation Center of Chinese Medicinal Resources Industrialization, National and Local Collaborative Engineering Center of Chinese Medicinal Resources Industrialization and Formulae Innovative Medicine, Nanjing University of Chinese Medicine, Nanjing 210023, China; Corresponding authors.Pancreatic cancer remains one of the cancers with the poorest prognosis bearing an overall 5-year survival rate of about 5%. Efficient new chemotherapic drugs are still highly desired. Here, bruceine A, a quassinoid identified from the dried fruits of Brucea javanica (L.) Merr., displayed the most potent anti-proliferation activity against pancreatic cancer in vitro and in vivo. Phosphoproteomic analysis revealed p38α MAPK phosphorylation was involved in bruceine A’s action in MIA PaCa-2 cells. Utilizing fortebio octet system and microscale thermophoresis, we found p38α MAPK had high affinity for bruceine A. Molecular docking and molecular dynamic simulations showed that bruceine A widely bound to residues (Leu171, Ala172, Met179, Thr180, Val183) in P-loop of p38α MAPK. Key determinants of bruceine A binding with P-loop of p38α MAPK were 19-CO, 22-CH3, 32-CH3, and 34-CH3. Taken together, our findings demonstrate that bruceine A binds directly to p38α MAPK, which can be used to probe the role of p38α MAPK phosphorylation in pancreatic cancer progression, and as a novel lead compound for pancreatic cancer therapy.http://www.sciencedirect.com/science/article/pii/S200103702100249XQuassinoidsBruceine APhosphoproteomicP38α MAPK activatorBinding affinityMolecular simulations |
| spellingShingle | Cai Lu Lu Fan Peng-Fei Zhang Wei-Wei Tao Cheng-Bin Yang Er-Xin Shang Fei-Yan Chen Chun-Tao Che Hai-Bo Cheng Jin-Ao Duan Ming Zhao A novel P38α MAPK activator Bruceine A exhibits potent anti-pancreatic cancer activity Computational and Structural Biotechnology Journal Quassinoids Bruceine A Phosphoproteomic P38α MAPK activator Binding affinity Molecular simulations |
| title | A novel P38α MAPK activator Bruceine A exhibits potent anti-pancreatic cancer activity |
| title_full | A novel P38α MAPK activator Bruceine A exhibits potent anti-pancreatic cancer activity |
| title_fullStr | A novel P38α MAPK activator Bruceine A exhibits potent anti-pancreatic cancer activity |
| title_full_unstemmed | A novel P38α MAPK activator Bruceine A exhibits potent anti-pancreatic cancer activity |
| title_short | A novel P38α MAPK activator Bruceine A exhibits potent anti-pancreatic cancer activity |
| title_sort | novel p38α mapk activator bruceine a exhibits potent anti pancreatic cancer activity |
| topic | Quassinoids Bruceine A Phosphoproteomic P38α MAPK activator Binding affinity Molecular simulations |
| url | http://www.sciencedirect.com/science/article/pii/S200103702100249X |
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