CX4945 suppresses the growth of castration-resistant prostate cancer cells by reducing AR-V7 expression
Chuangzhong Deng1,2,3, Jieping Chen1,2,3, Shengjie Guo1,2,3
1Department of Urology, Sun Yat-sen University Cancer Center, 651 Dongfeng East Road, Guangzhou, 510060, People's Republic of China.
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.
Insights
Inhibition of casein kinase 2 (CK2) with CX4945 suppresses castration-resistant prostate cancer (CRPC) cell viability by downregulating androgen receptor variant 7 (AR-V7). This restores sensitivity to anti-androgen therapy, offering a new treatment strategy for advanced prostate cancer.
Area of Science:
- Oncology
- Molecular Biology
- Biochemistry
Background:
- Aberrant casein kinase 2 (CK2) expression is linked to prostate cancer development and progression.
- CK2 inhibition impacts androgen receptor (AR) signaling in prostate cancer cells.
- Androgen receptor variants (ARVs) are crucial in castration-resistant prostate cancer (CRPC).
Purpose of the Study:
- To investigate the effects of CK2 inhibition on CRPC cells, focusing on AR variants.
- To evaluate the efficacy of the selective CK2 inhibitor CX4945 in CRPC models.
Main Methods:
- Utilized CCK8 and colony formation assays to assess cell proliferation.
- Quantified full-length AR (AR-FL) and AR-V7 mRNA and protein levels via qPCR and western blot.
- Assessed NF-κB pathway activity by measuring nuclear translocation of p50 and p65.
Main Results:
- CX4945 significantly reduced CRPC cell proliferation in a dose- and time-dependent manner.
- CX4945 downregulated both AR-V7 mRNA and protein levels, with minimal effect on AR-FL.
- CX4945 treatment restored CRPC cell sensitivity to bicalutamide and attenuated NF-κB pathway activity by inhibiting p65 phosphorylation.
Conclusions:
- CK2 inhibition via CX4945 effectively represses CRPC cell viability.
- Suppression of AR-V7 by CX4945 restores sensitivity to anti-androgen therapy.
- This approach presents a promising therapeutic strategy for prostate cancer, particularly CRPC.
