The novel ER stress inducer Sec C triggers apoptosis by sulfating ER cysteine residues and degrading YAP via ER stress in pancreatic cancer cells  

作　　者：Junxia Wang Minghua Chen Mengyan Wang Wenxia Zhao Conghui Zhang Xiujun Liu Meilian Cai Yuhan Qiu Tianshu Zhang Huimin Zhou Wuli Zhao Shuyi Si Rongguang Shao 

机构地区：[1]Key Laboratory of Antibiotic Bioengineering,Ministry of Health,Laboratory of Oncology,Institute of Medicinal Biotechnology,Chinese Academy of Medical Sciences and Peking Union Medical College,Beijing 100050,China

出　　处：《Acta Pharmaceutica Sinica B》2022年第1期210-227,共18页药学学报（英文版）

基　　金：supported by the National Key Research and Development Program of China(2016YFA0201504);National Natural Science Foundation of China(No.81473249 and81102464);the National Mega-project for Innovative Drugs(2014ZX09201042,China);the CAMS Innovation Fund for Medical Sciences(CIFMS,2016-I2M-2-002,China);Drug Innovation Major Project of China(2018ZX09711001-007-002)。

摘　　要：Pancreatic adenocarcinoma(PAAD) is one of the most lethal malignancies. Although gemcitabine(GEM) is a standard treatment for PAAD, resistance limits its application and therapy. Secoemestrin C(Sec C) is a natural compound from the endophytic fungus Emericella, and its anticancer activity has not been investigated since it was isolated. Our research is the first to indicate that Sec C is a broad-spectrum anticancer agent and could exhibit potently similar anticancer activity both in GEM-resistant and GEM-sensitive PAAD cells. Interestingly, Sec C exerted a rapid growth-inhibiting effect(80% death at 6 h), which might be beneficial for patients who need rapid tumor shrinkage before surgery. Liquid chromatography/mass spectrometry and N-acetyl-L-cysteine(NAC) reverse assays show that Sec C sulfates cysteines to disrupt disulfide-bonds formation in endoplasmic reticulum(ER) proteins to cause protein misfolding, leading to ER stress and disorder of lipid biosynthesis. Microarray data and subsequent assays show that ER stress-mediated ER-associated degradation(ERAD) ubiquitinates anddownregulates YAP to enhance ER stress via destruction complex(YAP-Axin-GSK-βTr CP), which also elucidates a unique degrading style for YAP. Potent anticancer activity in GEM-resistant cells and low toxicity make Sec C a promising anti-PAAD candidate.

关 键 词：Pancreatic cancer Secoemestrin C YAP degradation ER stress inducer Resistance Fast shrinkage YAP destruction complex Lipid droplet formation 

分 类 号：R735.9[医药卫生—肿瘤]