ATP citrate lyase inhibitor triggers endoplasmic reticulum stress to induce hepatocellular carcinoma cell apoptosis via p‐eIF2α/ATF4/CHOP axis
| العنوان: | ATP citrate lyase inhibitor triggers endoplasmic reticulum stress to induce hepatocellular carcinoma cell apoptosis via p‐eIF2α/ATF4/CHOP axis |
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| المؤلفون: | Yihu Zheng, Qingqing Zhou, Qiandong Zhu, Junjian Li, Chang Zhao, Zhengping Yu |
| المصدر: | Journal of Cellular and Molecular Medicine |
| بيانات النشر: | Wiley, 2021. |
| سنة النشر: | 2021 |
| مصطلحات موضوعية: | Male, 0301 basic medicine, ATP citrate lyase, Eukaryotic Initiation Factor-2, Apoptosis, CHOP, Mice, 0302 clinical medicine, Cell Movement, Enzyme Inhibitors, Gene knockdown, Chemistry, Liver Neoplasms, hepatocellular carcinoma, Middle Aged, Endoplasmic Reticulum Stress, Gene Expression Regulation, Neoplastic, Gene Knockdown Techniques, 030220 oncology & carcinogenesis, Molecular Medicine, Female, Original Article, Signal Transduction, medicine.drug, Adult, Sorafenib, Programmed cell death, Carcinoma, Hepatocellular, 03 medical and health sciences, Cell Line, Tumor, medicine, Animals, Humans, neoplasms, Aged, Cell Proliferation, Neoplasm Staging, Proportional Hazards Models, Cell growth, Gene Expression Profiling, ACLY inhibitor BMS‐303141, Original Articles, Cell Biology, Activating Transcription Factor 4, Xenograft Model Antitumor Assays, digestive system diseases, Disease Models, Animal, 030104 developmental biology, ATP Citrate (pro-S)-Lyase, Cancer research, Unfolded protein response, sorafenib, Transcriptome, Transcription Factor CHOP |
| الوصف: | ATP citrate lyase (ACLY), a key enzyme in the metabolic reprogramming of many cancers, is widely expressed in various mammalian tissues. This study aimed to evaluate the effects and mechanisms of ACLY and its inhibitor BMS‐303141 on hepatocellular carcinoma (HCC). In this study, ACLY was highly expressed in HCC tissues, especially in HepG2 and Huh7 cells, but was down‐regulated in Hep3B and HCC‐LM3 cells. Besides, ACLY knockdown inhibited HepG2 proliferation and clone formation, while opposite result was noticed in HCC‐LM3 cells with ACLY overexpression. Moreover, ACLY knockdown impeded the migration and invasion abilities of HepG2 cells. Similarly, BMS‐303141 suppressed HepG2 and Huh‐7 cell proliferation. The p‐eIF2α, ATF4, CHOP p‐IRE1α, sXBP1 and p‐PERK were activated in HepG2 cells stimulated by BMS‐303141. In cells where ER stress was induced, ATF4 was involved in BMS‐303141‐mediated cell death procession, and ATF4 knockdown reduced HCC cell apoptosis stimulated by BMS‐303141. In a mouse xenograft model, combined treatment with BMS‐303141 and sorafenib reduced HepG2 tumour volume and weight. In addition, ACLY expression was associated with HCC metastasis and tumour‐node‐metastases staging. Survival analysis and Cox proportional hazards regression model showed that overall survival was lower in HCC patients with high ACLY expression; AFP level, TNM staging, tumour size and ACLY expression level were independent risk factors affecting their overall survival. In conclusion, ACLY might represent a promising target in which BMS‐303141 could induce ER stress and activate p‐eIF2α/ATF4/CHOP axis to promote apoptosis of HCC cells, and synergized with sorafenib to enhance the efficacy of HCC treatment. |
| تدمد: | 1582-4934 1582-1838 |
| الوصول الحر: | https://explore.openaire.eu/search/publication?articleId=doi_dedup___::ffe388e85a87c34fb599b71c6d7c719bTest https://doi.org/10.1111/jcmm.16235Test |
| حقوق: | OPEN |
| رقم الانضمام: | edsair.doi.dedup.....ffe388e85a87c34fb599b71c6d7c719b |
| قاعدة البيانات: | OpenAIRE |
| تدمد: | 15824934 15821838 |
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