Suppression of steroid 5α-reductase type I promotes cellular apoptosis and autophagy via PI3K/Akt/mTOR pathway in multiple myeloma.
Suppression of steroid 5α-reductase type I promotes cellular apoptosis and autophagy via PI3K/Akt/mTOR pathway in multiple myeloma.
复制标题
DOI：
10.1038/s41419-021-03510-4
复制
发表时间：
2021-02-24
影响因子：
9
通讯作者：
Yang Y
中科院分区：
文献类型：
--
作者：
Dou R;Qian J;Wu W;Zhang Y;Yuan Y;Guo M;Wei R;Yang S;Jurczyszyn A;Janz S;Beksac M;Gu C;Yang Y
类固醇5α还原酶I型(SRD5A1)是一种在许多性激素相关癌症中被证实的癌基因，但其在多发性骨髓瘤(MM)中的作用尚不清楚。根据MM病程序贯样本的基因表达谱(GEP)，我们发现SRD5A1的异常表达与MM的进展和预后不良有关。在这项研究中，SRD5A1在人MM细胞系(ARP1和H929)和异种移植MM模型以及5TMM小鼠模型中的致癌作用得到了验证。采用四甲基偶氮唑盐比色法和流式细胞仪检测慢病毒介导的短发夹状RNA(ShRNA)可诱导的SRD5A1基因敲除后MM细胞的增殖、细胞周期和细胞凋亡。采用转录本测序、免疫荧光和免疫印迹等方法研究SRD5A1抑制对细胞凋亡和自噬的影响。在机制上，SRD5A1下调通过PI3K/Akt/mTor信号通路同时调控Bcl2家族蛋白介导的细胞凋亡和自噬过程。同时，用自噬抑制剂(3-甲基腺嘌呤)和SRD5A1抑制剂(杜他斯特胺)评价它们的抗骨髓瘤作用。因此，我们的结果表明，SRD5A1下调同时调节MM细胞的凋亡和自噬过程。自噬-凋亡双重调节基因SRD5A1可作为MM进展和预后的生物标志物和潜在靶点。
Steroid 5α-reductase type I (SRD5A1) is a validated oncogene in many sex hormone-related cancers, but its role in multiple myeloma (MM) remains unknown. Based on gene expression profiling (GEP) of sequential MM samples during the disease course, we found that the aberrant expression of SRD5A1 was correlated with progression and poor prognosis in MM patients. In this study, the oncogenic roles of SRD5A1 were validated in human MM cell lines (ARP1 and H929) and the xenograft MM model as well as the 5TMM mouse model. MTT and flow cytometry were used to assess MM cell proliferation, cell cycle, and apoptosis post inducible knockdown SRD5A1 by lentivirus-mediated short-hairpin RNA (shRNA). Transcriptomic sequencing, immunofluorescence, and western blot were used to investigate the effects of SRD5A1 suppression on cell apoptosis and autophagy. Mechanistically, SRD5A1 downregulation simultaneously regulated both the Bcl-2 family protein-mediated apoptosis and the autophagic process via PI3K/Akt/mTOR signaling pathway in MM cells. Meanwhile, the autophagy inhibitor (3-methyladenine) and SRD5A1 inhibitor (Dutasteride) were utilized to evaluate their anti-myeloma effect. Thus, our results demonstrated that SRD5A1 downregulation simultaneously regulated both the apoptosis and the autophagic process in MM cells. The dual autophagy–apoptosis regulatory SRD5A1 may serve as a biomarker and potential target for MM progression and prognosis.
登录
查看更多内容
影响因子：
3.7
作者：
Jernberg E;Thysell E;Bovinder Ylitalo E;Rudolfsson S;Crnalic S;Widmark A;Bergh A;Wikström P
通讯作者：
Wikström P
影响因子：
9.7
作者：
Jarauta, Vidal;Jaime, Paula;Naval, Javier
通讯作者：
Naval, Javier
影响因子：
6.5
作者：
Niesvizky, Ruben;Richardson, Paul G.;Blade, Joan
通讯作者：
Blade, Joan
影响因子：
3.7
作者：
Li J;Ding Z;Wang Z;Lu JF;Maity SN;Navone NM;Logothetis CJ;Mills GB;Kim J
通讯作者：
Kim J
DOI：
10.1016/0960-0760(90)90487-6
发表时间：
1990-11-20
影响因子：
4.1
作者：
STONER, E
通讯作者：
STONER, E