image: Secoemestrin C sulfates endoplasmic reticulum (ER) cysteines to disrupt disulfide-bonds formation in ER proteins, causing ER stress. Meanwhile, ER stress is cooperatively enhanced by ERAD-induced YAP degradation via YAP–Axin–GSK–βTrCP complex formation. view more
Credit: APSB
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. This research indicates 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 downregulates YAP to enhance ER stress via destruction complex (YAP–Axin–GSK–βTrCP), 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.
Article reference: Wang J, Chen M, Wang M, Zhao W, Zhang C, Liu X, Cai M, Qiu Y, ZhangT, Zhou H, Zhao W, Si S, Shao R, The novel ER stress inducer Sec C triggers apoptosis by sulphating ER cysteine residues and degrading YAP via ER stress in pancreatic cancer cells, Acta Pharmaceutica Sinica B, 2021, ISSN 2211-3835, https://doi.org/10.1016/j.apsb.2021.07.004
Keywords: Pancreatic cancer, Secoemestrin C, YAP degradation, ER stress inducer, Resistance, Fast shrinkage, YAP destruction complex, Lipid droplet formation
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The Journal of the Institute of Materia Medica, the Chinese Academy of Medical Sciences and the Chinese Pharmaceutical Association.
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CiteScore: 12.5
Impact Factor: 11.413
ISSN 2211-3835
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