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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

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Acta Pharmaceutica Sinica B 2022年第1期12卷 210-227页

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 Key Laboratory of Antibiotic Bioengineering Ministry of HealthLaboratory of OncologyInstitute of Medicinal BiotechnologyChinese Academy of Medical Sciences and Peking Union Medical CollegeBeijing 100050China

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

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Regenerating gene 4 promotes chemoresistance of colorectal cancer by affecting lipid droplet synthesis and assembly

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World Journal of Gastroenterology 2023年第35期29卷 5104-5124页

作者： Cong-Yu Zhang Rui Zhang Li Zhang Zi-Mo Wang Hong-Zhi Sun Zheng-Guo Cui Hua-Chuan Zheng Cancer Center The First Affiliated Hospital of Jinzhou Medical UniversityJinzhou 121001Liaoning ProvinceChina Department of Colorectal Surgery Liaoning Cancer HospitalShenyang 110042Liaoning ProvinceChina Department of Oncology The Affiliated Hospital of Chengde Medical UniversityChengde 067000Hebei ProvinceChina Department of Environmental Health University of Fukui School of Medical SciencesFukui 910-1193Japan

BACKGROUND Regenerating gene 4(REG4)has been proved to be carcinogenic in some cancers,but its manifestation and possible carcinogenic mechanisms in colorectal cancer(CRC)have not yet been *** previous study found that the drug resistance of CRC cells may be closely linked to their fat *** To explore the role of REG4 in CRC and its association with lipid droplet formation and *** We conducted a meta-analysis and bioinformatics and pathological analyses of REG4 expression in *** effects of REG4 on the phenotypes and related protein expression were also investigated in CRC *** detected the impacts of REG4 on the chemoresistance and lipid droplet formation in CRC ***,we analyzed how REG4 regulated the transcription and proteasomal degradation of lipogenic enzymes in CRC *** Compared to normal mucosa,REG4 mRNA expression was high in CRC(Plipid droplet ***4 inhibited the transcription of acetyl-CoA carboxylase 1(ACC1)and ATP-citrate lyase(ACLY)by disas

关键词： Colorectal cancer Regenerating gene 4 Aggressive behavior Prognosis Chemoresistance lipid droplet formation Epidermal growth factor receptor signal

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