NF-κB2/p52 induces resistance to enzalutamide in prostate cancer: role of androgen receptor and its variants.
NF-κB2/p52 induces resistance to enzalutamide in prostate cancer: role of androgen receptor and its variants.
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DOI：
10.1158/1535-7163.mct-13-0027
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发表时间：
2013-08
影响因子：
5.7
通讯作者：
Gao AC
中科院分区：
文献类型：
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作者：
Nadiminty N;Tummala R;Liu C;Yang J;Lou W;Evans CP;Gao AC
前列腺癌细胞对下一代抗雄激素Enzalutamide的耐药性可能由多种生存信号通路介导。在本研究中，我们检测了NF-κB2/p52表达增加是否诱导前列腺癌细胞对Enzalutamide耐药，以及这种应答是否由异常雄激素受体（AR）激活和AR剪接变体产生介导。Enzalutamide处理稳定表达NF-κB2/p52的LNCaP细胞时，其存活率高于对照组。发现Enzalutamide长期处理的C4-2B和CWR 22 Rv 1细胞表达较高水平的NF-κB2/p52。Enzalutamide长期处理的CWR 22 Rv 1细胞中NF-κB2/p52下调使其对Enzalutamide的细胞生长抑制更敏感。通过定量逆转录PCR和Western印迹分析AR剪接变体的表达水平，揭示表达p52的LNCaP细胞表现出更高的AR剪接变体表达。短发夹RNA下调VCaP和CWR 22 Rv 1细胞中NF-κB2/p52的表达，消除剪接变体的表达。全长AR或剪接变体AR-V7的表达下调导致前列腺癌细胞对Enzalutamide的敏感性增加。这些结果共同表明，Enzalutamide耐药可能由NF-κB2/p52通过激活AR及其剪接变体介导。
Resistance of prostate cancer cells to the next-generation antiandrogen enzalutamide may be mediated by a multitude of survival signaling pathways. In this study, we tested whether increased expression of NF-κB2/p52 induces prostate cancer cell resistance to enzalutamide and whether this response is mediated by aberrant androgen receptor (AR) activation and AR splice variant production. LNCaP cells stably expressing NF-κB2/p52 exhibited higher survival rates than controls when treated with enzalutamide. C4-2B and CWR22Rv1 cells chronically treated with enzalutamide were found to express higher levels of NF-κB2/p52. Downregulation of NF-κB2/p52 in CWR22Rv1 cells chronically treated with enzalutamide rendered them more sensitive to cell growth inhibition by enzalutamide. Analysis of the expression levels of AR splice variants by quantitative reverse transcription PCR and Western blotting revealed that LNCaP cells expressing p52 exhibit higher expression of AR splice variants. Downregulation of expression of NF-κB2/p52 in VCaP and CWR22Rv1 cells by short hairpin RNA abolished expression of splice variants. Downregulation of expression of either full-length AR or the splice variant AR-V7 led to an increase in sensitivity of prostate cancer cells to enzalutamide. These results collectively demonstrate that resistance to enzalutamide may be mediated by NF-κB2/p52 via activation of AR and its splice variants.