Chuangzhong Deng1,2,3, Jieping Chen1,2,3, Shengjie Guo1,2,3, Yanjun Wang1,2,3, Qianghua Zhou1,2,3, Zaishang Li1,2,3, Xingping Yang4, Xingsu Yu2,3,5, Zhenfeng Zhang2,3,5, Fangjian Zhou1,2,3, Hui Han6,7,8, Kai Yao9,10,11. 1. Department of Urology, Sun Yat-sen University Cancer Center, 651 Dongfeng East Road, Guangzhou, 510060, People's Republic of China. 2. State Key Laboratory of Oncology in Southern China, Guangzhou, People's Republic of China. 3. Collaborative Innovation Center of Cancer Medicine, Guangzhou, People's Republic of China. 4. Department of Laboratory Medicine, Sun Yat-sen University Cancer Center, Guangzhou, 510060, People's Republic of China. 5. Center of Medical Imaging and Image-guided Therapy, Sun Yat-sen University Cancer Center, Guangzhou, People's Republic of China. 6. Department of Urology, Sun Yat-sen University Cancer Center, 651 Dongfeng East Road, Guangzhou, 510060, People's Republic of China. hanhui@sysucc.org.cn. 7. State Key Laboratory of Oncology in Southern China, Guangzhou, People's Republic of China. hanhui@sysucc.org.cn. 8. Collaborative Innovation Center of Cancer Medicine, Guangzhou, People's Republic of China. hanhui@sysucc.org.cn. 9. Department of Urology, Sun Yat-sen University Cancer Center, 651 Dongfeng East Road, Guangzhou, 510060, People's Republic of China. yaokai@sysucc.org.cn. 10. State Key Laboratory of Oncology in Southern China, Guangzhou, People's Republic of China. yaokai@sysucc.org.cn. 11. Collaborative Innovation Center of Cancer Medicine, Guangzhou, People's Republic of China. yaokai@sysucc.org.cn.
Abstract
PURPOSE: The 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. METHODS: A 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. RESULTS: CX4945 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. CONCLUSION: The 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.
PURPOSE: The 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. METHODS: A 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. RESULTS: CX4945 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. CONCLUSION: The 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.
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