A novel P38α MAPK activator Bruceine A exhibits potent anti-pancreatic cancer activity
Cai Lu1, Lu Fan2, Peng-Fei Zhang1
1Jiangsu 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.
Abstract:
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-C[bond, double bond]O, 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.
Insights
Bruceine A shows potent anti-pancreatic cancer activity by directly binding to p38α MAPK. This natural compound offers a promising new therapeutic lead for pancreatic cancer treatment.
Area of Science:
- Oncology
- Pharmacology
- Molecular Biology
Background:
- Pancreatic cancer has a very poor prognosis with a 5-year survival rate of approximately 5%.
- There is a critical need for novel and effective chemotherapeutic agents for pancreatic cancer treatment.
Purpose of the Study:
- To investigate the anti-cancer properties of bruceine A, a quassinoid from Brucea javanica.
- To elucidate the molecular mechanism underlying bruceine A's action against pancreatic cancer cells.
- To evaluate bruceine A as a potential therapeutic lead for pancreatic cancer.
Main Methods:
- In vitro and in vivo assays to assess anti-proliferation activity.
- Phosphoproteomic analysis to identify molecular targets.
- Bio-physical techniques (forte-bio octet, microscale thermophoresis) to determine binding affinity.
- Molecular docking and dynamic simulations to analyze binding interactions.
Main Results:
- Bruceine A demonstrated significant anti-proliferation activity against pancreatic cancer cells.
- Phosphoproteomic analysis identified p38α MAPK phosphorylation as a key pathway involved in bruceine A's effects.
- Bruceine A exhibited high affinity for p38α MAPK, binding to specific residues in its P-loop.
- Molecular simulations detailed the binding interactions between bruceine A and p38α MAPK.
Conclusions:
- Bruceine A directly binds to p38α MAPK, suggesting a novel mechanism of action.
- Bruceine A can serve as a valuable tool to study p38α MAPK phosphorylation in pancreatic cancer.
- Bruceine A represents a promising novel lead compound for developing new pancreatic cancer therapies.
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