Skip to main content

Advertisement

SpringerLink
Log in

CX4945 suppresses the growth of castration-resistant prostate cancer cells by reducing AR-V7 expression

  • Original Article
  • Published:
World Journal of Urology Aims and scope Submit manuscript

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.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6

Similar content being viewed by others

References

  1. Siegel RL, Miller KD, Jemal A (2015) Cancer statistics, 2015. CA Cancer J Clin 65(1):5–29. doi:10.3322/caac.21254

    Article  PubMed  Google Scholar 

  2. Mostaghel EA, Montgomery B, Nelson PS (2009) Castration-resistant prostate cancer: targeting androgen metabolic pathways in recurrent disease. Urol Oncol 27(3):251–257. doi:10.1016/j.urolonc.2009.03.016

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Chen CD, Welsbie DS, Tran C, Baek SH, Chen R, Vessella R, Rosenfeld MG, Sawyers CL (2004) Molecular determinants of resistance to antiandrogen therapy. Nat Med 10(1):33–39. doi:10.1038/nm972

    Article  PubMed  Google Scholar 

  4. de Bono JS, Logothetis CJ, Molina A, Fizazi K, North S, Chu L, Chi KN, Jones RJ, Goodman OB Jr, Saad F, Staffurth JN, Mainwaring P, Harland S, Flaig TW, Hutson TE, Cheng T, Patterson H, Hainsworth JD, Ryan CJ, Sternberg CN, Ellard SL, Flechon A, Saleh M, Scholz M, Efstathiou E, Zivi A, Bianchini D, Loriot Y, Chieffo N, Kheoh T, Haqq CM, Scher HI (2011) Abiraterone and increased survival in metastatic prostate cancer. N Engl J Med 364(21):1995–2005. doi:10.1056/NEJMoa1014618

    Article  PubMed  PubMed Central  Google Scholar 

  5. Beer TM, Armstrong AJ, Rathkopf DE, Loriot Y, Sternberg CN, Higano CS, Iversen P, Bhattacharya S, Carles J, Chowdhury S, Davis ID, de Bono JS, Evans CP, Fizazi K, Joshua AM, Kim CS, Kimura G, Mainwaring P, Mansbach H, Miller K, Noonberg SB, Perabo F, Phung D, Saad F, Scher HI, Taplin ME, Venner PM, Tombal B (2014) Enzalutamide in metastatic prostate cancer before chemotherapy. N Engl J Med 371(5):424–433. doi:10.1056/NEJMoa1405095

    Article  PubMed  PubMed Central  Google Scholar 

  6. De Maeseneer DJ, Van Praet C, Lumen N, Rottey S (2015) Battling resistance mechanisms in antihormonal prostate cancer treatment: Novel agents and combinations. Urol Oncol 33(7):310–321. doi:10.1016/j.urolonc.2015.01.008

    Article  PubMed  Google Scholar 

  7. Robinson D, Van Allen EM, Wu YM, Schultz N, Lonigro RJ, Mosquera JM, Montgomery B, Taplin ME, Pritchard CC, Attard G, Beltran H, Abida W, Bradley RK, Vinson J, Cao X, Vats P, Kunju LP, Hussain M, Feng FY, Tomlins SA, Cooney KA, Smith DC, Brennan C, Siddiqui J, Mehra R, Chen Y, Rathkopf DE, Morris MJ, Solomon SB, Durack JC, Reuter VE, Gopalan A, Gao J, Loda M, Lis RT, Bowden M, Balk SP, Gaviola G, Sougnez C, Gupta M, Yu EY, Mostaghel EA, Cheng HH, Mulcahy H, True LD, Plymate SR, Dvinge H, Ferraldeschi R, Flohr P, Miranda S, Zafeiriou Z, Tunariu N, Mateo J, Perez-Lopez R, Demichelis F, Robinson BD, Schiffman M, Nanus DM, Tagawa ST, Sigaras A, Eng KW, Elemento O, Sboner A, Heath EI, Scher HI, Pienta KJ, Kantoff P, de Bono JS, Rubin MA, Nelson PS, Garraway LA, Sawyers CL, Chinnaiyan AM (2015) Integrative clinical genomics of advanced prostate cancer. Cell 161(5):1215–1228. doi:10.1016/j.cell.2015.05.001

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Montgomery RB, Mostaghel EA, Vessella R, Hess DL, Kalhorn TF, Higano CS, True LD, Nelson PS (2008) Maintenance of intratumoral androgens in metastatic prostate cancer: a mechanism for castration-resistant tumor growth. Cancer Res 68(11):4447–4454. doi:10.1158/0008-5472.can-08-0249

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Zengerling F, Azoitei A, Herweg A, Jentzmik F, Cronauer MV (2016) Inhibition of IGF-1R diminishes transcriptional activity of the androgen receptor and its constitutively active, C-terminally truncated counterparts Q640X and AR-V7. World J Urol 34(5):633–639. doi:10.1007/s00345-015-1674-5

    Article  CAS  PubMed  Google Scholar 

  10. Nakazawa M, Antonarakis ES, Luo J (2014) Androgen receptor splice variants in the era of enzalutamide and abiraterone. Horm Cancer 5 (5):265–273. doi:10.1007/s12672-014-0190-1

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Guo Z, Yang X, Sun F, Jiang R, Linn DE, Chen H, Chen H, Kong X, Melamed J, Tepper CG, Kung HJ, Brodie AM, Edwards J, Qiu Y (2009) A novel androgen receptor splice variant is up-regulated during prostate cancer progression and promotes androgen depletion-resistant growth. Cancer Res 69(6):2305–2313. doi:10.1158/0008-5472.can-08-3795

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Li Y, Chan SC, Brand LJ, Hwang TH, Silverstein KA, Dehm SM (2013) Androgen receptor splice variants mediate enzalutamide resistance in castration-resistant prostate cancer cell lines. Cancer Res 73(2):483–489. doi:10.1158/0008-5472.CAN-12-3630

    Article  CAS  PubMed  Google Scholar 

  13. Gietz RD, Graham KC, Litchfield DW (1995) Interactions between the subunits of casein kinase II. J Biol Chem 270(22):13017–13021

    Article  CAS  PubMed  Google Scholar 

  14. Montenarh M (2014) Protein kinase CK2 and angiogenesis. Adv Clin Exp Med 23 (2):153–158

    Article  PubMed  Google Scholar 

  15. Trembley JH, Wang G, Unger G, Slaton J, Ahmed K (2009) Protein kinase CK2 in health and disease: CK2: a key player in cancer biology. Cell Mol Life Sci CMLS 66 (11–12):1858–1867. doi:10.1007/s00018-009-9154-y

    Article  CAS  PubMed  Google Scholar 

  16. Yenice S, Davis AT, Goueli SA, Akdas A, Limas C, Ahmed K (1994) Nuclear casein kinase 2 (CK-2) activity in human normal, benign hyperplastic, and cancerous prostate. Prostate 24(1):11–16

    Article  CAS  PubMed  Google Scholar 

  17. Yoo JY, Lim BJ, Choi HK, Hong SW, Jang HS, Kim C, Chun KH, Choi KC, Yoon HG (2013) CK2-NCoR signaling cascade promotes prostate tumorigenesis. Oncotarget 4(7):972–983

    Article  PubMed  PubMed Central  Google Scholar 

  18. Yao K, Youn H, Gao X, Huang B, Zhou F, Li B, Han H (2012) Casein kinase 2 inhibition attenuates androgen receptor function and cell proliferation in prostate cancer cells. Prostate 72(13):1423–1430. doi:10.1002/pros.22493

    Article  CAS  PubMed  Google Scholar 

  19. Hessenauer A, Montenarh M, Gotz C (2003) Inhibition of CK2 activity provokes different responses in hormone-sensitive and hormone-refractory prostate cancer cells. Int J Oncol 22(6):1263–1270

    CAS  PubMed  Google Scholar 

  20. Krause WC, Shafi AA, Nakka M, Weigel NL (2014) Androgen receptor and its splice variant, AR-V7, differentially regulate FOXA1 sensitive genes in LNCaP prostate cancer cells. Int J Biochem Cell Biol 54:49–59. doi:10.1016/j.biocel.2014.06.013

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Romieu-Mourez R, Landesman-Bollag E, Seldin DC, Sonenshein GE (2002) Protein kinase CK2 promotes aberrant activation of nuclear factor-kappaB, transformed phenotype, and survival of breast cancer cells. Cancer Res 62(22):6770–6778

    CAS  PubMed  Google Scholar 

  22. Jaksch C, Thams P (2014) A critical role for CK2 in cytokine-induced activation of NFkappaB in pancreatic beta cell death. Endocr 47(1):117–128. doi:10.1007/s12020-013-0133-6

    Article  CAS  Google Scholar 

  23. Jin R, Yamashita H, Yu X, Wang J, Franco OE, Wang Y, Hayward SW, Matusik RJ (2014) Inhibition of NF-kappa B signaling restores responsiveness of castrate-resistant prostate cancer cells to anti-androgen treatment by decreasing androgen receptor-variant expression. Oncogene. doi:10.1038/onc.2014.302

    Google Scholar 

  24. Chatterjee A, Chatterjee U, Ghosh MK (2013) Activation of protein kinase CK2 attenuates FOXO3a functioning in a PML-dependent manner: implications in human prostate cancer. Cell Death Dis 4:e543. doi:10.1038/cddis.2013.63

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Sramkoski RM, Pretlow TG, 2nd, Giaconia JM, Pretlow TP, Schwartz S, Sy MS, Marengo SR, Rhim JS, Zhang D, Jacobberger JW (1999) A new human prostate carcinoma cell line, 22Rv1. In vitro Cell Dev Biol Anim 35 (7):403–409. doi:10.1007/s11626-999-0115-4

    Article  CAS  PubMed  Google Scholar 

  26. Tran C, Ouk S, Clegg NJ, Chen Y, Watson PA, Arora V, Wongvipat J, Smith-Jones PM, Yoo D, Kwon A, Wasielewska T, Welsbie D, Chen CD, Higano CS, Beer TM, Hung DT, Scher HI, Jung ME, Sawyers CL (2009) Development of a second-generation antiandrogen for treatment of advanced prostate cancer. Science 324(5928):787–790. doi:10.1126/science.1168175

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Yamashita S, Lai K-P, Chuang K-L, Xu D, Miyamoto H, Tochigi T, Pang S-T, Li L, Arai Y, Kung H-J, Yeh S, Chang C (2012) ASC-J9 suppresses castration-resistant prostate cancer growth through degradation of full-length and splice variant androgen receptors. Neoplasia 14(1):74–N12. doi:10.1593/neo.111436

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Setlur SR, Royce TE, Sboner A, Mosquera JM, Demichelis F, Hofer MD, Mertz KD, Gerstein M, Rubin MA (2007) Integrative microarray analysis of pathways dysregulated in metastatic prostate cancer. Cancer Res 67(21):10296–10303. doi:10.1158/0008-5472.can-07-2173

    Article  CAS  PubMed  Google Scholar 

  29. Jin R, Sterling JA, Edwards JR, DeGraff DJ, Lee C, Park SI, Matusik RJ (2013) Activation of NF-kappa B signaling promotes growth of prostate cancer cells in bone. PloS One 8(4):e60983. doi:10.1371/journal.pone.0060983

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Sun S, Sprenger CC, Vessella RL, Haugk K, Soriano K, Mostaghel EA, Page ST, Coleman IM, Nguyen HM, Sun H, Nelson PS, Plymate SR (2010) Castration resistance in human prostate cancer is conferred by a frequently occurring androgen receptor splice variant. J Clin Invest 120(8):2715–2730. doi:10.1172/jci41824

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

This work was supported by the National Natural Science Foundation of China (No. 81302224); the Xinjiang Uygur Autonomous Region Scientific and Technological Support Projects (No. 201491192).

Author information

Authors and Affiliations

  1. Department of Urology, Sun Yat-sen University Cancer Center, 651 Dongfeng East Road, Guangzhou, 510060, People’s Republic of China

    Chuangzhong Deng, Jieping Chen, Shengjie Guo, Yanjun Wang, Qianghua Zhou, Zaishang Li, Fangjian Zhou, Hui Han & Kai Yao

  2. State Key Laboratory of Oncology in Southern China, Guangzhou, People’s Republic of China

    Chuangzhong Deng, Jieping Chen, Shengjie Guo, Yanjun Wang, Qianghua Zhou, Zaishang Li, Xingsu Yu, Zhenfeng Zhang, Fangjian Zhou, Hui Han & Kai Yao

  3. Collaborative Innovation Center of Cancer Medicine, Guangzhou, People’s Republic of China

    Chuangzhong Deng, Jieping Chen, Shengjie Guo, Yanjun Wang, Qianghua Zhou, Zaishang Li, Xingsu Yu, Zhenfeng Zhang, Fangjian Zhou, Hui Han & Kai Yao

  4. Department of Laboratory Medicine, Sun Yat-sen University Cancer Center, Guangzhou, 510060, People’s Republic of China

    Xingping Yang

  5. Center of Medical Imaging and Image-guided Therapy, Sun Yat-sen University Cancer Center, Guangzhou, People’s Republic of China

    Xingsu Yu & Zhenfeng Zhang

Authors
  1. Chuangzhong Deng
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Jieping Chen
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Shengjie Guo
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Yanjun Wang
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Qianghua Zhou
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Zaishang Li
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Xingping Yang
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Xingsu Yu
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Zhenfeng Zhang
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Fangjian Zhou
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Hui Han
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. Kai Yao
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding authors

Correspondence to Hui Han or Kai Yao.

Ethics declarations

Conflict of interest

The authors declare that they have no conflict of interest

Additional information

C. Deng and J. Chen contributed equally to this research.

Electronic supplementary material

Below is the link to the electronic supplementary material.

Supplementary material 1 (DOCX 221 KB)

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Deng, C., Chen, J., Guo, S. et al. CX4945 suppresses the growth of castration-resistant prostate cancer cells by reducing AR-V7 expression. World J Urol 35, 1213–1221 (2017). https://doi.org/10.1007/s00345-016-1996-y

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00345-016-1996-y

Keywords

Search

Navigation