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AKR1C3/AR-V7 复合物通过抑制 B4GALT1 的表达来维持 CRPC 肿瘤的生长。

The AKR1C3/AR-V7 complex maintains CRPC tumour growth by repressing B4GALT1 expression.

机构信息

Department of Urology, First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China.

Department of Breast Surgery, First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China.

出版信息

J Cell Mol Med. 2020 Oct;24(20):12032-12043. doi: 10.1111/jcmm.15831. Epub 2020 Sep 9.

DOI:10.1111/jcmm.15831
PMID:32902124
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC7579719/
Abstract

Multiple mechanisms contribute to the survival and growth of metastatic castration-resistant prostate cancer (mCRPC) cells without androgen, including androgen receptor splice variants (AR-V) and de novo intratumoral androgen synthesis. AKR1C3 is a critical androgenic enzyme that plays different roles in mCRPC, such as an EMT driver or AR coactivator. However, the relationship and regulatory mechanisms between AKR1C3 and AR-V remain largely unknown. In this study, we observed a positive correlation between AKR1C3 and AR-V7 staining in tissues from prostate rebiopsy at mCRPC. Mechanistically, AKR1C3 interacts with AR-V7 protein in CRPC cells, which can reciprocally inhibit AR-V7 and AKR1C3 protein degradation. Biologically, this complex is essential for in vitro and in vivo tumour growth of CRPC cells after androgen deprivation as it represses B4GALT1, a unique tumour suppressor gene in PCa. Together, this study reveals AKR1C3/AR-V7 complex as a potential therapeutic target in mCRPC.

摘要

多种机制有助于无雄激素情况下转移性去势抵抗性前列腺癌 (mCRPC) 细胞的存活和生长，包括雄激素受体剪接变体 (AR-V) 和肿瘤内新合成的雄激素。AKR1C3 是一种关键的雄激素酶，在 mCRPC 中发挥不同的作用，如 EMT 驱动因子或 AR 共激活因子。然而，AKR1C3 和 AR-V 之间的关系和调节机制在很大程度上仍然未知。在这项研究中，我们观察到在 mCRPC 时前列腺再活检组织中 AKR1C3 和 AR-V7 染色之间存在正相关。在机制上，AKR1C3 在 CRPC 细胞中与 AR-V7 蛋白相互作用，这可以相互抑制 AR-V7 和 AKR1C3 蛋白降解。从生物学上讲，这种复合物对于去势后 CRPC 细胞的体外和体内肿瘤生长是必不可少的，因为它抑制了前列腺癌中独特的肿瘤抑制基因 B4GALT1。总之，这项研究揭示了 AKR1C3/AR-V7 复合物作为 mCRPC 的潜在治疗靶点。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/f7b1/7579719/83c52063955d/JCMM-24-12032-g008.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/f7b1/7579719/effe017f4b05/JCMM-24-12032-g001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/f7b1/7579719/3c46df53bfe7/JCMM-24-12032-g002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/f7b1/7579719/49e43e1615da/JCMM-24-12032-g003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/f7b1/7579719/04b18aa4479e/JCMM-24-12032-g004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/f7b1/7579719/24d814ceb999/JCMM-24-12032-g005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/f7b1/7579719/1ccafd089d83/JCMM-24-12032-g006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/f7b1/7579719/462e6f9470c8/JCMM-24-12032-g007.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/f7b1/7579719/83c52063955d/JCMM-24-12032-g008.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/f7b1/7579719/effe017f4b05/JCMM-24-12032-g001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/f7b1/7579719/3c46df53bfe7/JCMM-24-12032-g002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/f7b1/7579719/49e43e1615da/JCMM-24-12032-g003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/f7b1/7579719/04b18aa4479e/JCMM-24-12032-g004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/f7b1/7579719/24d814ceb999/JCMM-24-12032-g005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/f7b1/7579719/1ccafd089d83/JCMM-24-12032-g006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/f7b1/7579719/462e6f9470c8/JCMM-24-12032-g007.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/f7b1/7579719/83c52063955d/JCMM-24-12032-g008.jpg

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