Department of Urology, Tianjin Institute of Urology, The Second Hospital of Tianjin Medical University, Tianjin Medical University, Tianjin, 300211, China.
George Whipple Lab for Cancer Research, Departments of Pathology and Urology, University of Rochester Medical Center, Rochester, NY, 14642, USA.
J Exp Clin Cancer Res. 2021 Jan 4;40(1):3. doi: 10.1186/s13046-020-01760-2.
Early studies indicated that ASC-J9®, an androgen receptor (AR) degradation enhancer, could suppress the prostate cancer (PCa) progression. Here we found ASC-J9® could also suppress the PCa progression via an AR-independent mechanism, which might involve modulating the tumor suppressor ATF3 expression.
The lentiviral system was used to modify gene expression in C4-2, CWR22Rv1 and PC-3 cells. Western blot and Immunohistochemistry were used to detect protein expression. MTT and Transwell assays were used to test the proliferation and invasion ability.
ASC-J9® can suppress PCa cell proliferation and invasion in both PCa C4-2 and CWR22Rv1 cells via altering the ATF3 expression. Further mechanistic studies reveal that ASC-J9® can increase the ATF3 expression via decreasing Glutamate-cysteine ligase catalytic (GCLC) subunit expression, which can then lead to decrease the PTK2 expression. Human clinical studies further linked the ATF3 expression to the PCa progression. Preclinical studies using in vivo mouse model also proved ASC-J9® could suppress AR-independent PCa cell invasion, which could be reversed after suppressing ATF3.
ASC-J9® can function via altering ATF3/PTK2 signaling to suppress the PCa progression in an AR-independent manner.
早期研究表明，雄激素受体（AR）降解增强剂 ASC-J9®可以抑制前列腺癌（PCa）的进展。在这里，我们发现 ASC-J9®还可以通过 AR 非依赖性机制抑制 PCa 的进展，这可能涉及调节肿瘤抑制因子 ATF3 的表达。
使用慢病毒系统修饰 C4-2、CWR22Rv1 和 PC-3 细胞中的基因表达。Western blot 和免疫组化检测蛋白表达。MTT 和 Transwell 测定用于测试增殖和侵袭能力。
ASC-J9®可通过改变 ATF3 表达抑制 PCa C4-2 和 CWR22Rv1 细胞中的 PCa 细胞增殖和侵袭。进一步的机制研究表明，ASC-J9®可以通过降低谷氨酸-半胱氨酸连接酶催化亚基（GCLC）亚基的表达来增加 ATF3 的表达，从而导致 PTK2 的表达降低。人类临床研究进一步将 ATF3 表达与 PCa 进展联系起来。使用体内小鼠模型的临床前研究也证明 ASC-J9®可以抑制 AR 非依赖性 PCa 细胞侵袭，抑制 ATF3 后可逆转这种侵袭。
ASC-J9®可以通过改变 ATF3/PTK2 信号通路以 AR 非依赖性方式发挥作用，抑制 PCa 的进展。
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