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A novel methuosis inducer DZ-514 possesses antitumor activity via activation of ROS-MKK4-p38 axis in triple negative breast cancer

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收录情况： ◇ SCIE

作者：
Wang Luzhen[1,2] * ; Mi Dazhao[3] * ; Hu Jinhui[4] * ; Liu Wenjing[5] ; Zhang Yi[6] ; Wang Chunyan[7] ; Chen Yihua[3] ; Chen Ceshi[2,5,8,*1] ;
机构： [1]School of Life Science, University of Science & Technology of China, Hefei, 230027, Anhui, China [2]Key Laboratory of Animal Models and Human Disease Mechanisms of the Chinese Academy of Sciences and Yunnan Province, Kunming Institute of Zoology, Chinese Academy of Sciences, Kunming, 650201, China [3]Shanghai Frontiers Science Center of Genome Editing and Cell Therapy, Shanghai Key Laboratory of Regulatory Biology, Institute of Biomedical Sciences and School of Life Sciences, East China Normal University, Shanghai, 200241, China [4]The First Hospital of Hunan University of Chinese Medicine, Changsha, 410007, Hunan, China [5]The Third Affiliated Hospital, Kunming Medical University, Kunming, 650118, China [6]Department of Breast and Thyroid Surgery, Southwest Hospital, The First Affiliated Hospital of the Army Military Medical University, Chongqing, 400038, China [7]Department of the Pathology, First Affiliated Hospital of Kunming Medical University, Kunming, Yunnan, 650032, China [8]Academy of Biomedical Engineering, Kunming Medical University, Kunming, 650500, China
出处：
DOI： 10.1016/j.canlet.2022.216049
ISSN：

关键词： Methuosis Triple-negative breast cancer BCL6 Reactive oxygen species MKK4 p38

摘要：
Triple-negative breast cancer (TNBC) is one of the most malignant tumors with poor prognosis. Methuosis is a new type of nonapoptotic cell death characterized by the accumulation of cytoplasmic vacuoles. In this study, we synthesized and screened a series of N-phenyl-4-pyrimidinediamine derivatives in TNBC cells, finding that DZ-514 was the best compound with high toxicity independent of the inhibition of BCL6. DZ-514 decreased cell viability, inhibited cell cycle progression, and induced caspase-independent cell death in TNBC cells. Interestingly, DZ-514 induced cytoplasm vacuolation, which could be blocked by Baf A1, the V-ATPase inhibitor. Furthermore, we found that DZ-514-induced vacuoles were derived from macropinosomes rather than autophagosomes. Most importantly, methuosis induced by DZ-514 was partially mediated by activating the ROS-MKK4-p38 axis. Finally, we demonstrated that DZ-514 significantly inhibited tumor growth in an HCC1806 xenograft mouse model. These findings revealed that the novel methuosis inducer DZ-514 could be developed for TNBC treatment.Copyright © 2023 Elsevier B.V. All rights reserved.

基金：
This work was supported by the National Key R&D Program of China (No.2020YFA0112300), the National Natural Science Foundation of China (N0.82160461, 81830087, U2102203, and 81973160), the Yunnan Fundamental Research Projects (No.202101AS070050), the Major Projects for Fundamental Research of Yunnan Province (202201BC070002), and the Hunan Provincial Department of Education Fund (No.20A373, China).
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大类 | 1 区 医学
小类 | 2 区 肿瘤学
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Q1 ONCOLOGY
最新[2023]版：
Q1 ONCOLOGY

影响因子： 最新[2023版] 最新五年平均 出版当年[2023版] 出版当年五年平均 出版前一年[2022版]

第一作者：
第一作者机构： [1]School of Life Science, University of Science & Technology of China, Hefei, 230027, Anhui, China [2]Key Laboratory of Animal Models and Human Disease Mechanisms of the Chinese Academy of Sciences and Yunnan Province, Kunming Institute of Zoology, Chinese Academy of Sciences, Kunming, 650201, China
共同第一作者：
通讯作者：
通讯机构： [2]Key Laboratory of Animal Models and Human Disease Mechanisms of the Chinese Academy of Sciences and Yunnan Province, Kunming Institute of Zoology, Chinese Academy of Sciences, Kunming, 650201, China [5]The Third Affiliated Hospital, Kunming Medical University, Kunming, 650118, China [8]Academy of Biomedical Engineering, Kunming Medical University, Kunming, 650500, China [*1]Academy of Biomedical Engineering, Kunming Medical University, Kunming, 650500, China.
推荐引用方式(GB/T 7714)：
Wang Luzhen,Mi Dazhao,Hu Jinhui,et al.A novel methuosis inducer DZ-514 possesses antitumor activity via activation of ROS-MKK4-p38 axis in triple negative breast cancer[J].CANCER LETTERS.2023,555:doi:10.1016/j.canlet.2022.216049.
APA：
Wang Luzhen,Mi Dazhao,Hu Jinhui,Liu Wenjing,Zhang Yi...&Chen Ceshi.(2023).A novel methuosis inducer DZ-514 possesses antitumor activity via activation of ROS-MKK4-p38 axis in triple negative breast cancer.CANCER LETTERS,555,
MLA：
Wang Luzhen,et al."A novel methuosis inducer DZ-514 possesses antitumor activity via activation of ROS-MKK4-p38 axis in triple negative breast cancer".CANCER LETTERS 555.(2023)

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