CX4945 suppresses the growth of castration-resistant prostate cancer cells by reducing AR-V7 expression
CX4945 suppresses the growth of castration-resistant prostate cancer cells by reducing AR-V7 expression
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CX4945 通过降低 AR-V7 表达来抑制去势抵抗性前列腺癌细胞的生长
DOI：
10.1007/s00345-016-1996-y
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发表时间：
2017-08-01
影响因子：
3.4
通讯作者：
Yao, Kai
中科院分区：
文献类型：
--
作者：
Deng, Chuangzhong;Chen, Jieping;Yao, Kai
目的研究酪蛋白激酶2（casein kinase 2，CK 2）的异常表达与前列腺癌的发生、发展有关。CK 2活性的抑制通过减弱雄激素受体（AR）信号通路来抑制雄激素依赖性前列腺癌细胞。在这项研究中，我们研究了抑制CK 2在去势抵抗性前列腺癌（CRPC）细胞中的作用，其中AR变体（ARVs）发挥了主导作用。方法利用一种新合成的CK 2选择性抑制剂CX 4945，通过CCK 8测定和集落形成试验研究CK 2抑制CRPC细胞的作用。全长AR（AR-FL）和AR-V7的蛋白质和mRNA水平分别通过qPCR和蛋白质印迹测定。结果CX4945可抑制CRPC细胞增殖，并呈剂量和时间依赖性。CX4945在mRNA和蛋白水平下调AR-V7而非AR-FL。此外，CX 4945可以恢复CRPC细胞对比卡鲁胺的敏感性。结论CX4945抑制CK 2可通过抑制AR-V7，抑制CRPC细胞活力，恢复CRPC细胞对抗雄激素治疗的敏感性。这一发现为治疗前列腺癌，特别是CRPC提供了一种潜在的选择。
PurposeThe aberrant expression of casein kinase 2 (CK2) has been reported to be involved in the tumorigenesis and progression of prostate cancer. The inhibition of CK2 activity represses androgen-dependent prostate cancer cells by attenuating the androgen receptor (AR) signaling pathway. In this study, we examined the effect of CK2 inhibition in castration-resistant prostate cancer (CRPC) cells, in which AR variants (ARVs) play a predominant role.MethodsA newly synthetic CK2 selective inhibitor CX4945 was utilized to study the effect of CK2 inhibition in CRPC cells by CCK8 assay and colony formation assay. Protein and mRNA levels of full-length AR (AR-FL) and AR-V7 were determined by qPCR and western blot, respectively. The nuclear translocation of p50 and p65 was assessed to reflect the activity of the NF-κB pathway.ResultsCX4945 reduced the proliferation of CRPC cells in a dose-dependent and time-dependent manner. AR-V7 rather than AR-FL was downregulated by CX4945 in both the mRNA and protein level. Furthermore, CX4945 could restore the sensitivity of CRPC cells to bicalutamide. The analysis of possible mechanisms demonstrated that the inhibition of CK2 diminished the phosphorylation of p65 at ser529 and thus attenuated the activity of the NF-κB pathway.ConclusionThe inhibition of CK2 by CX4945 can repress the viability of CRPC cells and restore their sensitivity to anti-androgen therapy by suppressing AR-V7. This finding presents a potential option for the treatment of prostate cancer, especially CRPC.