Targeting PHB1 to inhibit castration-resistant prostate cancer progression in vitro and in vivo.
Targeting PHB1 to inhibit castration-resistant prostate cancer progression in vitro and in vivo.
复制标题
DOI：
10.1186/s13046-023-02695-0
复制
发表时间：
2023-05-20
期刊：
影响因子：
--
通讯作者：
中科院分区：
文献类型：
--
作者：
去势抵抗性前列腺癌（CRPC）是目前前列腺癌（PCa）治疗面临的主要挑战，迫切需要寻找新的治疗靶点和药物。Prohibitin（PHB 1）是一种多功能伴侣/支架蛋白，在多种癌症中上调并发挥促癌作用。FL 3是一种合成的黄曲霉素药物，通过靶向PHB 1抑制癌细胞增殖。然而，PHB 1在CRPC中的生物学功能以及FL 3对CRPC细胞的影响仍有待于进一步研究。使用几个公共数据集来分析PHB 1表达水平与PCa进展以及PCa患者结局之间的关系。通过免疫组织化学（IHC）、qRT-PCR和Western blot检测人PCa标本和PCa细胞系中PHB 1的表达。通过功能获得/丧失分析研究了PHB 1在去势抵抗中的生物学作用及其潜在机制。接下来，进行体外和体内实验以研究FL 3对CRPC细胞的抗癌作用以及潜在的机制。PHB 1表达在CRPC中显著上调，与预后不良相关。PHB 1促进雄激素剥夺条件下PCa细胞的去势抵抗。PHB 1是一种雄激素受体（AR）抑制基因，雄激素剥夺促进PHB 1的表达及其核质易位。FL 3单独或与第二代抗雄激素Enzalutamide（ENZ）联合使用，在体外和体内均抑制CRPC细胞，尤其是对ENZ敏感的CRPC细胞。在机制上，我们证明FL 3促进PHB 1从质膜和线粒体运输到细胞核，这反过来又抑制AR信号传导以及MAPK信号传导，但促进CRPC细胞的凋亡。我们的数据表明，PHB 1在CRPC中异常上调，并参与去势抵抗，以及为治疗ENZ敏感的CRPC提供了一种新的合理方法。在线版本包含补充材料，可通过10.1186/s13046-023-02695-0获得。
Castration-resistant prostate cancer (CRPC) is currently the main challenge for prostate cancer (PCa) treatment, and there is an urgent need to find novel therapeutic targets and drugs. Prohibitin (PHB1) is a multifunctional chaperone/scaffold protein that is upregulated in various cancers and plays a pro-cancer role. FL3 is a synthetic flavagline drug that inhibits cancer cell proliferation by targeting PHB1. However, the biological functions of PHB1 in CRPC and the effect of FL3 on CRPC cells remain to be explored. Several public datasets were used to analyze the association between the expression level of PHB1 and PCa progression as well as outcome in PCa patients. The expression of PHB1 in human PCa specimens and PCa cell lines was examined by immunohistochemistry (IHC), qRT-PCR, and Western blot. The biological roles of PHB1 in castration resistance and underlying mechanisms were investigated by gain/loss-of-function analyses. Next, in vitro and in vivo experiments were conducted to investigate the anti-cancer effects of FL3 on CRPC cells as well as the underlying mechanisms. PHB1 expression was significantly upregulated in CRPC and was associated with poor prognosis. PHB1 promoted castration resistance of PCa cells under androgen deprivation condition. PHB1 is an androgen receptor (AR) suppressive gene, and androgen deprivation promoted the PHB1 expression and its nucleus-cytoplasmic translocation. FL3, alone or combined with the second-generation anti-androgen Enzalutamide (ENZ), suppressed CRPC cells especially ENZ-sensitive CRPC cells both in vitro and in vivo. Mechanically, we demonstrated that FL3 promoted trafficking of PHB1 from plasma membrane and mitochondria to nucleus, which in turn inhibited AR signaling as well as MAPK signaling, yet promoted apoptosis in CRPC cells. Our data indicated that PHB1 is aberrantly upregulated in CRPC and is involved in castration resistance, as well as providing a novel rational approach for treating ENZ-sensitive CRPC. The online version contains supplementary material available at 10.1186/s13046-023-02695-0.
登录
查看更多内容
影响因子：
5.6
作者：
Kobayashi T;Inoue T;Kamba T;Ogawa O
通讯作者：
Ogawa O
影响因子：
9.7
作者：
Jamroze A;Chatta G;Tang DG
通讯作者：
Tang DG
DOI：
10.1186/s13046-019-1440-4
发表时间：
2019-11-04
影响因子：
11.3
作者：
Bentayeb, Hafidha;Aitamer, Marine;Troutaud, Danielle
通讯作者：
Troutaud, Danielle
影响因子：
4.8
作者：
Fusaro, G;Dasgupta, P;Chellappan, S
通讯作者：
Chellappan, S
DOI：
10.1056/nejmoa1315815
发表时间：
2014-09-11
期刊：
The New England journal of medicine
影响因子：
--
作者：
Antonarakis ES;Lu C;Wang H;Luber B;Nakazawa M;Roeser JC;Chen Y;Mohammad TA;Chen Y;Fedor HL;Lotan TL;Zheng Q;De Marzo AM;Isaacs JT;Isaacs WB;Nadal R;Paller CJ;Denmeade SR;Carducci MA;Eisenberger MA;Luo J
通讯作者：
Luo J