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天然化合物阿特拉酸通过血管生成素 2 抑制雄激素调节的去势抵抗性前列腺癌新血管生成。

The natural compound atraric acid suppresses androgen-regulated neo-angiogenesis of castration-resistant prostate cancer through angiopoietin 2.

机构信息

Institute of Human Genetics, Jena University Hospital, Jena, 07740, Germany.

Leibniz Institute on Aging, Jena, 07745, Germany.

出版信息

Oncogene. 2022 Jun;41(23):3263-3277. doi: 10.1038/s41388-022-02333-7. Epub 2022 May 5.

DOI:10.1038/s41388-022-02333-7
PMID:35513564
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC9166678/
Abstract

Castration-resistant prostate cancer (CRPC) is an aggressive lethal form of prostate cancer (PCa). Atraric acid (AA) not only inhibits the wild-type androgen receptor (AR) but also those AR mutants that confer therapy resistance to other clinically used AR antagonists, indicating a different mode of AR antagonism. AA induces cellular senescence and inhibits CRPC tumour growth in in vivo xenograft mouse model associated with reduced neo-angiogenesis suggesting the repression of intratumoural neo-angiogenesis by AA. In line with this, the secretome of CRPC cells mediates neo-angiogenesis in an androgen-dependent manner, which is counteracted by AA. This was confirmed by two in vitro models using primary human endothelial cells. Transcriptome sequencing revealed upregulated angiogenic pathways by androgen, being however VEGF-independent, and pointing to the pro-angiogenic factor angiopoietin 2 (ANGPT2) as a key driver of neo-angiogenesis induced by androgens and repressed by AA. In agreement with this, AA treatment of native patient-derived PCa tumour samples ex vivo inhibits ANGPT2 expression. Mechanistically, in addition to AA, immune-depletion of ANGPT2 from secretome or blocking ANGPT2-receptors inhibits androgen-induced angiogenesis. Taken together, we reveal a VEGF-independent ANGPT2-mediated angiogenic pathway that is inhibited by AA leading to repression of androgen-regulated neo-angiogenesis.

摘要

去势抵抗性前列腺癌（CRPC）是一种侵袭性致命形式的前列腺癌（PCa）。阿特拉酸（AA）不仅抑制野生型雄激素受体（AR），而且抑制那些赋予其他临床使用的 AR 拮抗剂治疗耐药性的 AR 突变体，表明 AR 拮抗作用的不同模式。AA 诱导细胞衰老，并抑制体内异种移植小鼠模型中的 CRPC 肿瘤生长，与新生血管形成减少相关，表明 AA 抑制肿瘤内新生血管形成。与此一致的是，CRPC 细胞的分泌组以雄激素依赖的方式介导新生血管形成，AA 可拮抗这种作用。这通过使用原代人内皮细胞的两种体外模型得到了证实。转录组测序显示雄激素上调了血管生成途径，但与 VEGF 无关，并指出血管生成因子血管生成素 2（ANGPT2）是雄激素诱导的新生血管形成的关键驱动因素，并被 AA 抑制。与此一致的是，AA 处理体外原代患者来源的 PCa 肿瘤样本可抑制 ANGPT2 的表达。从机制上讲，除了 AA 之外，从分泌组中免疫耗竭 ANGPT2 或阻断 ANGPT2 受体也可抑制雄激素诱导的血管生成。综上所述，我们揭示了一种 VEGF 独立的 ANGPT2 介导的血管生成途径，AA 可抑制该途径，从而抑制雄激素调节的新生血管形成。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8ee6/9166678/a85deb902cd7/41388_2022_2333_Fig8_HTML.jpg
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https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8ee6/9166678/a85deb902cd7/41388_2022_2333_Fig8_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8ee6/9166678/f7496c3cd8fa/41388_2022_2333_Fig1_HTML.jpg
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https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8ee6/9166678/f0b0ec9b2f7f/41388_2022_2333_Fig5_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8ee6/9166678/94233a9c7421/41388_2022_2333_Fig6_HTML.jpg
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