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

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

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

Author: Junxia WANG ¹ ; Minghua CHEN ¹ ; Mengyan WANG ¹ ; Wenxia ZHAO ¹ ; Conghui ZHANG ¹ ; Xiujun LIU ¹ ; Meilian CAI ¹ ; Yuhan QIU ¹ ; Tianshu ZHANG ¹ ; Huimin ZHOU ¹ ; Wuli ZHAO ¹ ; Shuyi SI ¹ ; Rongguang SHAO ¹
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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.
Publication Type:Journal Article
Keywords: ER stress inducer; Fast shrinkage; Lipid droplet formation; Pancreatic cancer; Resistance; Secoemestrin C; YAP degradation; YAP destruction complex
From: Acta Pharmaceutica Sinica B 2022;12(1):210-227
CountryChina
Language:English
Abstract: 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-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.