Erzurumlu Yalcin, Dogan Hatice Kubra, Catakli Deniz, Aydogdu Esra, Muhammed Muhammed Tilahun
Department of Biochemistry, Faculty of Pharmacy, Suleyman Demirel University, 32260, Isparta, Turkey.
Department of Bioengineering, Institute of Science, Suleyman Demirel University, 32260, Isparta, Turkey.
J Cell Commun Signal. 2023 Sep;17(3):793-811. doi: 10.1007/s12079-022-00720-z. Epub 2023 Jan 25.
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. The present model of the impact of estrogens on ERAD and UPR signaling in androgen-sensitive prostate cancer cells.
前列腺癌的致瘤特性受高级激素调节介导的复杂分子信号调控。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）定位的蛋白质质量控制机制，包括内质网相关降解（ERAD）和未折叠蛋白反应（UPR）信号通路，有助于前列腺癌的发生和耐药性的发展。还确定这些系统受雄激素严格调控。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未完全了解。在此，我们研究了雌激素对ERAD和UPR的调控作用及其对前列腺癌发生的影响。我们发现雌激素通过Erα/β/AR轴强烈调节ERAD成分和UPR的IRE1α分支。此外，雌激素信号通过促进c-Myc表达和上皮-间质转化（EMT）严格调控前列腺癌细胞的致瘤性。而且，雌激素信号阻断显著降低了前列腺癌细胞的致瘤特征。此外，同时抑制雄激素/雌激素信号更有效地抑制了前列腺癌细胞的致瘤性，包括增殖、迁移、侵袭和集落生长。此外，基于计算的分子对接、分子动力学模拟和MMPBSA计算支持了雌激素对AR的刺激作用。目前的研究结果表明，ERAD成分和IRE1α信号受雌激素刺激的AR和Erα/β严格调控。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开发前列腺癌的新治疗方法铺平道路。雌激素对雄激素敏感的前列腺癌细胞中ERAD和UPR信号影响的当前模型。
