Bioengineered BERA-Wnt5a siRNA Targeting Wnt5a/FZD2 Signaling Suppresses Advanced Prostate Cancer Tumor Growth and Enhances Enzalutamide Treatment.
Bioengineered BERA-Wnt5a siRNA Targeting Wnt5a/FZD2 Signaling Suppresses Advanced Prostate Cancer Tumor Growth and Enhances Enzalutamide Treatment.
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DOI：
10.1158/1535-7163.mct-22-0216
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发表时间：
2022-10-07
影响因子：
5.7
通讯作者：
中科院分区：
文献类型：
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作者：
下一代抗雄激素药物如恩杂鲁胺和阿比特龙延长了晚期前列腺癌患者的生存时间并改善了生活质量。然而，对这两种药物的耐药性经常通过不完全了解的机制发生。Wnt信号，特别是通过Wnt5a，在促进前列腺癌进展和诱导对恩杂鲁胺和阿比特龙的耐药中起着至关重要的作用。迫切需要开发针对Wnt5a的新策略来克服耐药性。在本研究中，我们证实了Wnt5a/ fzd2介导的非规范Wnt通路在enzalutamide耐药前列腺癌中过表达。在患者数据库中，Wnt5a和FZD2的表达水平在恩杂鲁胺耐药的发展过程中上调，并与更高的Gleason评分、生化复发和转移状态以及缩短的无病生存期相关。阻断Wnt5a/FZD2信号转导不仅可以抑制非典型Wnt信号通路的激活，还可以抑制组成型激活的AR和AR变体。此外，我们开发了一种新的生物工程BERA-Wnt5a siRNA构建物，并证明了BERA-Wnt5a siRNA抑制Wnt5a表达可显著抑制肿瘤生长并增强体内enzalutamide治疗。这些结果表明，Wnt5a/FZD2信号通路在促进enzalutamide耐药中起关键作用，通过BERA-Wnt5a siRNA靶向该通路可作为治疗晚期前列腺癌的潜在疗法。
The next-generation antiandrogen drugs such as enzalutamide and abiraterone extend survival times and improve quality of life in patients with advanced prostate cancer. However, resistance to both drugs occurs frequently through mechanisms which are incompletely understood. Wnt signaling, particularly through Wnt5a, plays vital roles in promoting prostate cancer progression and induction of resistance to enzalutamide and abiraterone. Development of novel strategies targeting Wnt5a to overcome resistance is an urgent need. In this study, we demonstrated that Wnt5a/FZD2-mediated non-canonical Wnt pathway is overexpressed in enzalutamide resistant prostate cancer. In patient databases, both the levels of Wnt5a and FZD2 expression are upregulated upon the development of enzalutamide resistance and correlate with higher Gleason score, biochemical recurrence and metastatic status, and with shortened disease-free survival duration. Blocking Wnt5a/FZD2 signal transduction not only diminished the activation of non-canonical Wnt signaling pathway, but also suppressed the constitutively activated AR and AR variants. Furthermore, we developed a novel bioengineered BERA-Wnt5a siRNA construct and demonstrated that inhibition of Wnt5a expression by the BERA-Wnt5a siRNA significantly suppressed tumor growth and enhanced enzalutamide treatment in vivo. These results indicate that Wnt5a/FZD2 signal pathway plays critical role in promoting enzalutamide resistance and targeting this pathway by BERA-Wnt5a siRNA can be developed as a potential therapy to treat advanced prostate cancer.
寡核苷酸药物中的靶向mRNA抑制。
影响因子：
14.9
作者：
Lightfoot HL;Hall J
通讯作者：
Hall J