雌激素通过雄激素受体/雌激素受体信号传导驱动内质网相关降解,促进前列腺癌细胞中原癌基因c-Myc的表达

IF 3.6 3区 生物学 Q3 CELL BIOLOGY
Yalcin Erzurumlu, Hatice Kubra Dogan, Deniz Catakli, Esra Aydogdu, Muhammed Tilahun Muhammed
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引用次数: 2

摘要

前列腺癌的致瘤性是由激素调控介导的复杂分子信号调控的。因此,表征这些信号转导系统的调控对于理解前列腺癌生物学至关重要。最近的研究表明,内质网(ER)定位的蛋白质量控制机制,包括ER相关降解(ERAD)和未折叠蛋白反应(UPR)信号,有助于前列腺癌的发生和耐药的发展。研究还确定,这些系统受到雄激素的严格调控。然而,雌激素信号在前列腺癌中的作用及其对蛋白质质量控制机制的影响尚不完全清楚。在此,我们研究了雌激素对ERAD和UPR的调节作用及其对前列腺癌发生的影响。我们发现雌激素通过Er /β/AR轴强烈调节ERAD成分和UPR的IRE1分支。此外,雌激素信号通过促进c-Myc表达和上皮间质转化(epithelial-mesenchymal transition, EMT),严格调节前列腺癌细胞的致瘤性。此外,雌激素信号阻断显著降低前列腺癌细胞的致瘤性特征。此外,同时抑制雄激素/雌激素信号更有效地抑制前列腺癌细胞的致瘤性,包括增殖、迁移、侵袭和殖民生长。此外,基于计算的分子对接、分子动力学模拟和MMPBSA计算支持雌激素对AR的刺激。目前的研究结果表明,雌激素刺激的AR和Er /β密切调节ERAD成分和IRE1信号。我们的数据表明,针对雄激素/雌激素信号共同抑制的治疗方法可能为前列腺癌的新治疗方法的开发铺平道路。
本文章由计算机程序翻译,如有差异,请以英文原文为准。

Estrogens drive the endoplasmic reticulum-associated degradation and promote proto-oncogene c-Myc expression in prostate cancer cells by androgen receptor/estrogen receptor signaling

Estrogens drive the endoplasmic reticulum-associated degradation and promote proto-oncogene c-Myc expression in prostate cancer cells by androgen receptor/estrogen receptor signaling

The tumorigenic properties of prostate cancer are regulated by advanced hormonal regulation-mediated complex molecular signals. Therefore, characterizing the regulation of these signal transduction systems is crucial for understanding prostate cancer biology. Recent studies have shown that endoplasmic reticulum (ER)-localized protein quality control mechanisms, including ER-associated degradation (ERAD) and unfolded protein response (UPR) signaling contribute to prostate carcinogenesis and to the development of drug resistance. It has also been determined that these systems are tightly regulated by androgens. However, the role of estrogenic signaling in prostate cancer and its effects on protein quality control mechanisms is not fully understood. Herein, we investigated the regulatory effects of estrogens on ERAD and UPR and their impacts on prostate carcinogenesis. We found that estrogens strongly regulated the ERAD components and IRE1⍺ branch of UPR by Er⍺/β/AR axis. Besides, estrogenic signaling rigorously regulated the tumorigenicity of prostate cancer cells by promoting c-Myc expression and epithelial-mesenchymal transition (EMT). Moreover, estrogenic signal blockage significantly decreased the tumorigenic features of prostate cancer cells. Additionally, simultaneous inhibition of androgenic/estrogenic signals more efficiently inhibited tumorigenicity of prostate cancer cells, including proliferation, migration, invasion and colonial growth. Furthermore, computational-based molecular docking, molecular dynamics simulations and MMPBSA calculations supported the estrogenic stimulation of AR. Present findings suggested that ERAD components and IRE1⍺ signaling are tightly regulated by estrogen-stimulated AR and Er⍺/β. Our data suggest that treatment approaches targeting the co-inhibition of androgenic/estrogenic signals may pave the way for new treatment approaches to be developed for prostate cancer.

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来源期刊
CiteScore
6.40
自引率
4.90%
发文量
40
期刊介绍: The Journal of Cell Communication and Signaling provides a forum for fundamental and translational research. In particular, it publishes papers discussing intercellular and intracellular signaling pathways that are particularly important to understand how cells interact with each other and with the surrounding environment, and how cellular behavior contributes to pathological states. JCCS encourages the submission of research manuscripts, timely reviews and short commentaries discussing recent publications, key developments and controversies. Research manuscripts can be published under two different sections : In the Pathology and Translational Research Section (Section Editor Andrew Leask) , manuscripts report original research dealing with celllular aspects of normal and pathological signaling and communication, with a particular interest in translational research. In the Molecular Signaling Section (Section Editor Satoshi Kubota) manuscripts report original signaling research performed at molecular levels with a particular interest in the functions of intracellular and membrane components involved in cell signaling.
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