使用 Z-FY-CHO 抑制剂靶向前列腺和乳腺癌细胞中的核组织蛋白酶 L CCAAT 置换蛋白/切割同源盒转录因子-上皮间充质转化途径。,Molecular and Cellular Biology

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使用 Z-FY-CHO 抑制剂靶向前列腺和乳腺癌细胞中的核组织蛋白酶 L CCAAT 置换蛋白/切割同源盒转录因子-上皮间充质转化途径。
Molecular and Cellular Biology ( IF 3.2 ) Pub Date : 2017-02-15 , DOI: 10.1128/mcb.00297-16
Liza J Burton ₁ , Jodi Dougan ₁ , Jasmine Jones ₁ , Bethany N Smith ₁ , Diandra Randle ₁ , Veronica Henderson ₁ , Valerie A Odero-Marah ₂

Affiliation

上皮间充质转化（EMT）通过下调上皮标志物（如 E-钙粘蛋白）和上调间充质标志物（如波形蛋白）来促进肿瘤迁移和侵袭。组织蛋白酶 L (Cat L) 是一种半胱氨酸蛋白酶，可以通过蛋白水解激活 CCAAT 置换蛋白/切割同源盒转录因子 (CUX1)。我们假设核 Cat L 可能通过 CUX1 促进 EMT，并且这可能会被 Cat L 特异性抑制剂 Z-FY-CHO 拮抗。间充质前列腺（ARCaP-M 和 ARCaP-E 过表达 Snail）和乳腺癌（MDA-MB-468、MDA-MB-231 和 MCF-7 过表达 Snail）癌细胞表达较低的 E-钙粘蛋白活性，较高的 Snail、波形蛋白和与上皮前列腺（ARCaP-E 和 ARCaP-Neo）和乳腺癌（MCF-7 和 MCF-7 Neo）癌细胞相比，Cat L 活性和 p110/p90 活性 CUX1 形式。与上皮前列腺和乳腺细胞相比，间充质细胞中 CUX1 与 Snail 和 E-钙粘蛋白启动子的结合增加。用 Cat L 抑制剂 Z-FY-CHO 处理间充质细胞导致 Cat L 从核到细胞质的重新定位，减少 CUX1 与 Snail 和 E-钙粘蛋白启动子的结合，逆转 EMT，并减少细胞迁移/侵袭。总体而言，我们的新数据表明 Snail-核 Cat L-CUX1 之间的正反馈回路驱动 EMT，这可以被 Z-FY-CHO 拮抗。因此，Z-FY-CHO 可能是对抗 EMT 和癌症进展的重要治疗工具。用 Cat L 抑制剂 Z-FY-CHO 处理间充质细胞导致 Cat L 从核到细胞质的重新定位，减少 CUX1 与 Snail 和 E-钙粘蛋白启动子的结合，逆转 EMT，并减少细胞迁移/侵袭。总体而言，我们的新数据表明 Snail-核 Cat L-CUX1 之间的正反馈回路驱动 EMT，这可以被 Z-FY-CHO 拮抗。因此，Z-FY-CHO 可能是对抗 EMT 和癌症进展的重要治疗工具。用 Cat L 抑制剂 Z-FY-CHO 处理间充质细胞导致 Cat L 从核到细胞质的重新定位，减少 CUX1 与 Snail 和 E-钙粘蛋白启动子的结合，逆转 EMT，并减少细胞迁移/侵袭。总体而言，我们的新数据表明 Snail-核 Cat L-CUX1 之间的正反馈回路驱动 EMT，这可以被 Z-FY-CHO 拮抗。因此，Z-FY-CHO 可能是对抗 EMT 和癌症进展的重要治疗工具。

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Targeting the Nuclear Cathepsin L CCAAT Displacement Protein/Cut Homeobox Transcription Factor-Epithelial Mesenchymal Transition Pathway in Prostate and Breast Cancer Cells with the Z-FY-CHO Inhibitor.

The epithelial mesenchymal transition (EMT) promotes tumor migration and invasion by downregulating epithelial markers such as E-cadherin and upregulating mesenchymal markers such as vimentin. Cathepsin L (Cat L) is a cysteine protease that can proteolytically activate CCAAT displacement protein/cut homeobox transcription factor (CUX1). We hypothesized that nuclear Cat L may promote EMT via CUX1 and that this could be antagonized with the Cat L-specific inhibitor Z-FY-CHO. Mesenchymal prostate (ARCaP-M and ARCaP-E overexpressing Snail) and breast (MDA-MB-468, MDA-MB-231, and MCF-7 overexpressing Snail) cancer cells expressed lower E-cadherin activity, higher Snail, vimentin, and Cat L activity, and a p110/p90 active CUX1 form, compared to epithelial prostate (ARCaP-E and ARCaP-Neo) and breast (MCF-7 and MCF-7 Neo) cancer cells. There was increased binding of CUX1 to Snail and the E-cadherin promoter in mesenchymal cells compared to epithelial prostate and breast cells. Treatment of mesenchymal cells with the Cat L inhibitor Z-FY-CHO led to nuclear-to-cytoplasmic relocalization of Cat L, decreased binding of CUX1 to Snail and the E-cadherin promoter, reversed EMT, and decreased cell migration/invasion. Overall, our novel data suggest that a positive feedback loop between Snail-nuclear Cat L-CUX1 drives EMT, which can be antagonized by Z-FY-CHO. Therefore, Z-FY-CHO may be an important therapeutic tool to antagonize EMT and cancer progression.

更新日期：2019-11-01

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