Login to Access Video or Poster Abstract: MP87-20
Sources of Funding: This work was supported by JSPS KAKENHI Grant Number 15K20109 and 26861299.

Introduction

Recently, several new drugs have been approved for castration-resistant prostate cancer (CRPC) patients, including the next generation anti-androgen enzalutamide (ENZ). However, survival benefits with ENZ are limited, and progression on ENZ is inevitable. We analyzed the gene expression profile of an ENZ-resistant CRPC cell line and identified BCL-6 as a potential therapeutic target.

Methods

Three cell lines were used: LNCaP, a human prostate cancer cell line that exhibits androgen-dependent proliferation; C4-2, an ENZ-sensitive CRPC cell line; and C4-2AT6, an ENZ-resistant CRPC cell line which had been established by incubating C4-2 in androgen ablation conditions. We performed whole genome expression analysis and explored gene profile changes among the three cell lines.

Results

Whole genome expression analysis by CGH array and Exome demonstrated that BCL-6 expression was higher in the order C4-2AT6 > C4-2 > LNCaP. We validated these results using western blotting. The protein expression level of BCL-6 was also higher in C4-2AT6 cells._x000D_ We evaluated the cytotoxic effect of a BCL-6 inhibitor, 79-6, on C4-2AT6 cells. Relative cell viability when treated with 10 ?M 79-6 was 65.7 ± 0.8%. Western blotting revealed that 79-6 promoted p53 expression and PARP cleavage in C4-2AT6 cells. We also examined the effect of BCL-6 inhibition by gene knockdown with siRNA. Knockdown of BCL-6 significantly reduces the cell viability of C4-2AT6 cells (78.4 ± 1.4%)._x000D_ Next, we examined the sensitivity of LNCaP and C4-2AT6 cells to ENZ. Relative cell viability when treated with 1 ?M ENZ was 73.6 ± 1.2% and 93.3 ± 2.7%, respectively. C4-2AT6 cells exhibited ENZ resistance. We examined the synergistic effect of ENZ and 79-6 on C4-2AT6 cells. The relative cell viability when treated with 1 ?M ENZ and 10 ?M 79-6 was 43.5 ± 2.1%._x000D_

Conclusions

BCL-6 inhibition was able to overcome ENZ resistance in CRPC cell lines.

Funding

This work was supported by JSPS KAKENHI Grant Number 15K20109 and 26861299.