| Autor: |
Wang, Junxia, Chen, Minghua, Wang, Mengyan, Zhao, Wenxia, Zhang, Conghui, Liu, Xiujun, Cai, Meilian, Qiu, Yuhan, Zhang, Tianshu, Zhou, Huimin, Zhao, Wuli, Si, Shuyi, Shao, Rongguang |
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| Zdroj: |
Acta Pharmaceutica Sinica B; Jan2022, Vol. 12 Issue 1, p210-227, 18p |
| Abstrakt: |
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 downregulates YAP to enhance ER stress via destruction complex (YAP–Axin–GSK– β TrCP), 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. 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– β TrCP complex formation. [Display omitted] [ABSTRACT FROM AUTHOR] |
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