胰腺癌
MAPK/ERK通路
体内
p38丝裂原活化蛋白激酶
磷酸化
体外
癌症研究
对接(动物)
化学
生物
癌症
生物化学
医学
内科学
生物技术
护理部
作者
Lu Cai,Lu Fan,Pengfei Zhang,Weiwei Tao,Chengbin Yang,Erxin Shang,Feiyan Chen,Chun‐Tao Che,Haibo Cheng,Jin‐Ao Duan,Ming Zhao
标识
DOI:10.1016/j.csbj.2021.06.011
摘要
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.
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