期刊
ACTA PHARMACEUTICA SINICA B
卷 12, 期 1, 页码 210-227出版社
INST MATERIA MEDICA, CHINESE ACAD MEDICAL SCIENCES
DOI: 10.1016/j.apsb.2021.07.004
关键词
Pancreatic cancer; Secoemestrin C; YAP degradation; ER stress inducer; Resistance; Fast shrinkage; YAP destruction complex; Lipid droplet formation
资金
- National Key Research and Development Program of China [2016YFA0201504]
- National Natural Science Foundation of China [81473249, 81102464]
- National Mega-project for Innovative Drugs, China [2014ZX09201042]
- CAMS Innovation Fund for Medical Sciences (CIFMS, China) [2016-I2M-2-002]
- Drug Innovation Major Project of China [2018ZX09711001-007-002]
Secoemestrin C (Sec C) is a potent broad-spectrum anticancer agent that exhibits rapid growth-inhibiting effects on pancreatic adenocarcinoma cells. Its mechanism of action involves sulfating cysteines to disrupt disulfide bonds formation in endoplasmic reticulum proteins, leading to protein misfolding and ER stress.
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 and
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