LW-213 induces cell apoptosis in human cutaneous T-cell lymphomas by activating PERK–eIF2α–ATF4–CHOP axis
| العنوان: | LW-213 induces cell apoptosis in human cutaneous T-cell lymphomas by activating PERK–eIF2α–ATF4–CHOP axis |
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| المؤلفون: | Zhanyu Wang, Po Hu, Xiangyuan Wang, Hongzheng Wang, Mengyuan Zhu, Qinglong Guo, Hui Li, Hui Hui, Yingjie Qing, Jia-rong Wang, Xiaoxuan Yu, Jingyan Xu |
| المصدر: | Acta Pharmacol Sin |
| بيانات النشر: | Springer Science and Business Media LLC, 2020. |
| سنة النشر: | 2020 |
| مصطلحات موضوعية: | 0301 basic medicine, Skin Neoplasms, T cell, Eukaryotic Initiation Factor-2, Antineoplastic Agents, Apoptosis, Mice, SCID, CHOP, Article, Inhibitory Concentration 50, Mice, eIF-2 Kinase, 03 medical and health sciences, 0302 clinical medicine, Mice, Inbred NOD, Cell Line, Tumor, hemic and lymphatic diseases, medicine, Animals, Humans, Pharmacology (medical), Pharmacology, Dose-Response Relationship, Drug, Chemistry, Myeloid leukemia, General Medicine, medicine.disease, Activating Transcription Factor 4, Xenograft Model Antitumor Assays, Lymphoma, T-Cell, Cutaneous, Lymphoma, Leukemia, 030104 developmental biology, medicine.anatomical_structure, Cell culture, 030220 oncology & carcinogenesis, Flavanones, Unfolded protein response, Cancer research, Female, Reactive Oxygen Species, Transcription Factor CHOP |
| الوصف: | Cutaneous T-cell lymphoma (CTCL) is characterized by a heterogeneous group of extranodal non-Hodgkin lymphomas, in which monoclonal T lymphocytes infiltrate the skin. LW-213, a derivative of wogonin, was found to induce cell apoptosis in chronic myeloid leukemia (CML). In this study, we investigated the effects of LW-213 on CTCL cells and the underlying mechanisms. We showed that LW-213 (1–25 μM) dose-dependently inhibited human CTCL cell lines (Hut-102, Hut-78, MyLa, and HH) with IC(50) values of around 10 μM, meanwhile it potently inhibited primary leukemia cells derived from peripheral blood of T-cell lymphoma patients. We revealed that LW-213-induced apoptosis was accompanied by ROS formation and the release of calcium from endoplasmic reticulum (ER) through IP(3)R-1channel. LW-213 selectively activated CHOP and induced apoptosis in Hut-102 cells via activating PERK–eIF2α–ATF4 pathway. Interestingly, the degree of apoptosis and expression of ER stress-related proteins were alleviated in the presence of either N-acetyl cysteine (NAC), an ROS scavenger, or 2-aminoethyl diphenylborinate (2-APB), an IP(3)R-1 inhibitor, implicating ROS/calcium-dependent ER stress in LW-213-induced apoptosis. In NOD/SCID mice bearing Hut-102 cell line xenografts, administration of LW-213 (10 mg/kg, ip, every other day for 4 weeks) markedly inhibited the growth of Hut-102 derived xenografts and prolonged survival. In conclusion, our study provides a new insight into the mechanism of LW-213-induced apoptosis, suggesting the potential of LW-213 as a promising agent against CTCL. |
| تدمد: | 1745-7254 1671-4083 |
| DOI: | 10.1038/s41401-020-0466-7 |
| URL الوصول: | https://explore.openaire.eu/search/publication?articleId=doi_dedup___::0a99012aa830853d8e6e79a2a9d04dfe https://doi.org/10.1038/s41401-020-0466-7 |
| Rights: | OPEN |
| رقم الانضمام: | edsair.doi.dedup.....0a99012aa830853d8e6e79a2a9d04dfe |
| قاعدة البيانات: | OpenAIRE |
| تدمد: | 17457254 16714083 |
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| DOI: | 10.1038/s41401-020-0466-7 |