Regulation of the EGFR Pathway by HSP90 Is Involved in the Pathogenesis of Cushing's Disease.
Regulation of the EGFR Pathway by HSP90 Is Involved in the Pathogenesis of Cushing's Disease.
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HSP90 对 EGFR 通路的调节参与库欣病的发病机制
DOI：
10.3389/fendo.2020.601984
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发表时间：
2020
影响因子：
5.2
通讯作者：
Ma Z
中科院分区：
文献类型：
--
作者：
Shen Y;Ji C;Jian X;Zhou J;Zhang Q;Qiao N;Zhang Y;Shou X;Zhou X;Ma Z
探讨热休克蛋白Hsp90在促肾上腺皮质激素（ACTH）分泌细胞中的作用，并探讨Hsp90抑制剂17- n -烯丙基氨基-17-去甲氧基格尔达霉素（17-AAG）在促肾上腺皮质瘤（又称“库欣病”（CD））中的潜在临床应用。采用小鼠垂体肿瘤[at -20/D16v-F2 （ATCC®CRL-1795™）]细胞和人垂体acth分泌肿瘤细胞培养。采用肝癌细胞系（HLE）评价17-AAG对EGFR的抑制作用。使用商业试剂盒评估细胞活力。放射免疫法测定ACTH水平。采用逆转录定量聚合酶链反应（RT-qPCR）检测POMC mRNA的表达。Western blotting检测蛋白水平。17-AAG抑制at -20/D16v-F2细胞的活力和增殖，促进细胞凋亡。17-AAG抑制at -20/D16v-F2细胞ACTH的合成和分泌，下调POMC转录。17-AAG对人垂体acth分泌肿瘤细胞的作用模式类似。17-AAG对携带泛素特异性蛋白酶8 （USP8）突变体的人垂体acth分泌肿瘤细胞的抑制作用强于携带野生型USP8的细胞。HSP90抑制剂17-AAG降低人垂体acth分泌肿瘤细胞的活力和分泌功能，携带USP8突变体的肿瘤细胞比携带野生型USP8的肿瘤细胞对17-AAG更敏感。17-AAG可能是乳糜泻的潜在治疗选择。
To investigate the role of heat-shock protein Hsp90 in adrenocorticotropic hormone (ACTH)-secreting cells, and to explore the potential clinical application of an inhibitor of Hsp90, 17-N-allylamino-17-demethoxygeldanamycin(17-AAG) in corticotropinomas [also known as “Cushing’s disease” (CD)]. Culture of mouse pituitary tumor [AtT-20/D16v-F2 (ATCC® CRL-1795™)] cells and human pituitary ACTH-secreting tumor cells were employed. Hepatocellular carcinoma cell line (HLE) was used to evaluate EGFR inhibition by 17-AAG. Cell viability was evaluated using a commercial kit. The ACTH level was measured by a radioimmunoassay. Reverse transcription quantitative polymerase chain reaction (RT-qPCR) was used to measure expression of proopiomelanocortin (POMC) mRNA. Western blotting was done to measure protein levels. 17-AAG suppressed the viability and proliferation, and promoted the apoptosis, of AtT-20/D16v-F2 cells. 17-AAG suppressed the synthesis and secretion of ACTH in AtT-20/D16v-F2 cells and down-regulated POMC transcription. 17-AAG acted in a similar pattern upon treatment with human pituitary ACTH-secreting tumor cells. Inhibition by 17-AAG was stronger in human pituitary ACTH-secreting tumor cells carrying the ubiquitin-specific protease-8 (USP8) mutant in comparison with cells carrying wild-type USP8. The HSP90 inhibitor 17-AAG reduced the viability and secretory function of human pituitary ACTH-secreting tumor cells, and tumor cells carrying the USP8 mutant were more sensitive to 17-AAG than tumor cells carrying wild-type USP8. 17-AAG could be a potential treatment option for CD.
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库欣病中反复出现功能获得性 USP8 突变。
影响因子：
44.1
作者：
通讯作者：
--
影响因子：
5.8
作者：
Castinetti, Frederic;Guignat, Laurence;Brue, Thierry
通讯作者：
Brue, Thierry
DOI：
10.1016/j.clml.2011.03.027
发表时间：
2011-06-01
期刊：
Clinical lymphoma, myeloma & leukemia
影响因子：
--
作者：
Usmani, Saad Z;Chiosis, Gabriela
通讯作者：
Chiosis, Gabriela
DOI：
10.1158/1078-0432.ccr-11-1000
发表时间：
2012-01-01
期刊：
Clinical cancer research : an official journal of the American Association for Cancer Research
影响因子：
--
作者：
Neckers L;Workman P
通讯作者：
Workman P
DOI：
10.1210/jc.2015-2616
发表时间：
2015-11
期刊：
The Journal of clinical endocrinology and metabolism
影响因子：
--
作者：
Daniel E;Aylwin S;Mustafa O;Ball S;Munir A;Boelaert K;Chortis V;Cuthbertson DJ;Daousi C;Rajeev SP;Davis J;Cheer K;Drake W;Gunganah K;Grossman A;Gurnell M;Powlson AS;Karavitaki N;Huguet I;Kearney T;Mohit K;Meeran K;Hill N;Rees A;Lansdown AJ;Trainer PJ;Minder AE;Newell-Price J
通讯作者：
Newell-Price J