Asteltoxin inhibits extracellular vesicle production through AMPK/mTOR-mediated activation of lysosome function.
Asteltoxin inhibits extracellular vesicle production through AMPK/mTOR-mediated activation of lysosome function.
复制标题
DOI：
10.1038/s41598-022-10692-0
复制
发表时间：
2022-04-23
影响因子：
4.6
通讯作者：
Oneyama, Chitose
中科院分区：
文献类型：
--
作者：
Mitani, Fumie;Lin, Jianyu;Sakamoto, Tatsuya;Uehara, Ryo;Hikita, Tomoya;Yoshida, Takuya;Setiawan, Andi;Arai, Masayoshi;Oneyama, Chitose
癌细胞分泌异常大量的细胞外囊泡（EVs），包括起源于多泡体（MVBs）的外泌体。由于EV可能促进肿瘤进展，因此EV抑制剂作为一种新的治疗方法备受关注。我们筛选了一个真菌天然产物库。利用癌细胞分泌荧光素酶标记的EV，我们发现了抑制线粒体ATP合酶的asteltoxin作为EV抑制剂。低浓度星藻毒素抑制EV分泌，但不引起线粒体损伤。Asteltoxin降低细胞ATP水平，诱导ampk介导的mTORC1失活。因此，MiT/TFE转录因子易位到细胞核中，促进溶酶体基因的转录和溶酶体的激活。电镜分析显示，用星霉素或雷帕霉素（一种mTORC1抑制剂）治疗后，溶酶体数量相对于MVBs增加，EVs水平下降。这些发现表明星形毒素是一种控制MVB命运的新型EV抑制剂。
Cancer cells secrete aberrantly large amounts of extracellular vesicles (EVs) including exosomes, which originate from multivesicular bodies (MVBs). Because EVs potentially contribute to tumor progression, EV inhibitors are of interest as novel therapeutics. We screened a fungal natural product library. Using cancer cells engineered to secrete luciferase-labeled EVs, we identified asteltoxin, which inhibits mitochondrial ATP synthase, as an EV inhibitor. Low concentrations of asteltoxin inhibited EV secretion without inducing mitochondrial damage. Asteltoxin attenuated cellular ATP levels and induced AMPK-mediated mTORC1 inactivation. Consequently, MiT/TFE transcription factors are translocated into the nucleus, promoting transcription of lysosomal genes and lysosome activation. Electron microscopy analysis revealed that the number of lysosomes increased relative to that of MVBs and the level of EVs decreased after treatment with asteltoxin or rapamycin, an mTORC1 inhibitor. These findings suggest that asteltoxin represents a new type of EV inhibitor that controls MVB fate.
登录
查看更多内容
影响因子：
4.6
作者：
Hikita T;Miyata M;Watanabe R;Oneyama C
通讯作者：
Oneyama C
影响因子：
5.6
作者：
Pópulo H;Lopes JM;Soares P
通讯作者：
Soares P
影响因子：
21.3
作者：
Costa-Silva B;Aiello NM;Ocean AJ;Singh S;Zhang H;Thakur BK;Becker A;Hoshino A;Mark MT;Molina H;Xiang J;Zhang T;Theilen TM;García-Santos G;Williams C;Ararso Y;Huang Y;Rodrigues G;Shen TL;Labori KJ;Lothe IM;Kure EH;Hernandez J;Doussot A;Ebbesen SH;Grandgenett PM;Hollingsworth MA;Jain M;Mallya K;Batra SK;Jarnagin WR;Schwartz RE;Matei I;Peinado H;Stanger BZ;Bromberg J;Lyden D
通讯作者：
Lyden D
影响因子：
4.6
作者：
Novaes, Antonio da Silva;Borges, Fernanda Teixeira;Boim, Mirian Aparecida
通讯作者：
Boim, Mirian Aparecida
影响因子：
16.6
作者：
Feng Q;Zhang C;Lum D;Druso JE;Blank B;Wilson KF;Welm A;Antonyak MA;Cerione RA
通讯作者：
Cerione RA