Endothelial nitric oxide synthase (eNOS)-NO signaling axis functions to promote the growth of prostate cancer stem-like cells.
Endothelial nitric oxide synthase (eNOS)-NO signaling axis functions to promote the growth of prostate cancer stem-like cells.
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内皮一氧化氮合酶（eNOS）-NO信号轴发挥促进前列腺癌干样细胞生长的作用
DOI：
10.1186/s13287-022-02864-6
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发表时间：
2022-05-07
影响因子：
7.5
通讯作者：
中科院分区：
文献类型：
--
作者：
越来越多的证据表明，前列腺癌干细胞样细胞（PCSCs）在前列腺癌的耐药和转移中起重要作用。许多研究还表明，由NO合成酶合成的一氧化氮（NO）可起到促进肿瘤进展的作用。然而，NOS和NO信号在PCSC和去势抵抗性前列腺癌（CRPC）生长调节中的确切作用仍不完全清楚。 在前列腺癌细胞中评估NOS-NO信号传导的调节功能，特别是在通过三维球体培养和CD 133/CD 44细胞分选富集的PCSC中。在PCSCs和小鼠原位前列腺肿瘤模型中研究NOS-NO信号在PCSCs生长调节和肿瘤转移中的分子机制。内皮型一氧化氮合酶（eNOS）在高级别前列腺癌和转移性CRPC中表现出显著上调。CRPC的异种移植模型表现出显著增加的eNOS表达和更高的细胞内NO水平。从各种模型中分离的PCSC显示出显著增强的eNOS-NO信号传导。功能分析表明，eNOS表达增加，可促进前列腺癌细胞在体内的致瘤性和转移潜力。对eNOS-NO下游信号通路的研究证实，eNOS信号通路的增强可通过激活下游的NO-sGC-cGMP-PKG效应信号通路促进PCSCs和抗雄激素抵抗前列腺癌细胞的生长。在前列腺癌细胞和PCSC中，核受体ERRα和转录因子ERG可以共同靶向eNOS的表达。增强的eNOS-NO信号通路可促进PCSC的生长，也可促进转移性CRPC的发展。除eNOS-NO作为潜在靶点外，靶向其上游调控因子ERRα和ERG也可能成为治疗晚期前列腺癌，尤其是携带TMPRSS 2：ERG融合基因的侵袭性前列腺癌的治疗策略。在线版本包含补充材料，可通过10.1186/s13287-022-02864-6获得。
Accumulating evidence supports that prostate cancer stem-like cells (PCSCs) play significant roles in therapy resistance and metastasis of prostate cancer. Many studies also show that nitric oxide (NO) synthesized by NO synthases can function to promote tumor progression. However, the exact roles of NOSs and NO signaling in the growth regulation of PCSCs and castration-resistant prostate cancer (CRPC) are still not fully understood. The regulatory functions of NOS-NO signaling were evaluated in prostate cancer cells, especially in PCSCs enriched by 3D spheroid culture and CD133/CD44 cell sorting. The molecular mechanisms of NOS-NO signaling in PCSCs growth regulation and tumor metastasis were investigated in PCSCs and mice orthotopic prostate tumor model. Endothelial NOS (eNOS) exhibited a significant upregulation in high-grade prostate cancer and metastatic CRPC. Xenograft models of CRPC exhibited notable increased eNOS expression and higher intracellular NO levels. PCSCs isolated from various models displayed significant enhanced eNOS-NO signaling. Functional analyses demonstrated that increased eNOS expression could promote in vivo tumorigenicity and metastatic potential of prostate cancer cells. Characterization of eNOS-NO involved downstream pathway which confirmed that enhanced eNOS signaling could promote the growth of PCSCs and antiandrogen-resistant prostate cancer cells via an activated downstream NO-sGC-cGMP-PKG effector signaling pathway. Interestingly, eNOS expression could be co-targeted by nuclear receptor ERRα and transcription factor ERG in prostate cancer cells and PCSCs. Enhanced eNOS-NO signaling could function to promote the growth of PCSCs and also the development of metastatic CRPC. Besides eNOS-NO as potential targets, targeting its upstream regulators (ERRα and ERG) of eNOS-NO signaling could also be the therapeutic strategy for the management of advanced prostate cancer, particularly the aggressive cancer carrying with the TMPRSS2:ERG fusion gene. The online version contains supplementary material available at 10.1186/s13287-022-02864-6.
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影响因子：
37.3
作者：
Gasch C;Ffrench B;O'Leary JJ;Gallagher MF
通讯作者：
Gallagher MF
影响因子：
7.5
作者：
Gao W;Wu D;Wang Y;Wang Z;Zou C;Dai Y;Ng CF;Teoh JY;Chan FL
通讯作者：
Chan FL
影响因子：
50.3
作者：
Domingo-Domenech J;Vidal SJ;Rodriguez-Bravo V;Castillo-Martin M;Quinn SA;Rodriguez-Barrueco R;Bonal DM;Charytonowicz E;Gladoun N;de la Iglesia-Vicente J;Petrylak DP;Benson MC;Silva JM;Cordon-Cardo C
通讯作者：
Cordon-Cardo C
影响因子：
5.8
作者：
Cheung, CP;Yu, S;Chan, FL
通讯作者：
Chan, FL
影响因子：
4.7
作者：
Lee, Kyoung-Mu;Kang, Daehee;Hayes, Richard B.
通讯作者：
Hayes, Richard B.