Department of Pharmacology and Toxicology, Faculty of Pharmacy, Ain Shams University, Cairo 11566, Egypt; Chapman University School of Pharmacy, Irvine, CA 92618, USA; School of Medicine, University of California, Irvine, CA, USA.
College of Pharmacy, University of Sharjah, Sharjah 27272, United Arab Emirates; Department of Pharmacology and Toxicology, Faculty of Pharmacy, Beni-Suef University, Beni-Suef, 62511 Egypt; Sharjah Institute for Medical Research, University of Sharjah, Sharjah 27272, United Arab Emirates.
Mol Cell Endocrinol. 2019 May 15;488:79-88. doi: 10.1016/j.mce.2019.03.007. Epub 2019 Mar 21.
Estrogen (E2) plays a central role in the development and progression of hormone-responsive cancers. Estrogen metabolites exhibit either stimulatory or inhibitory roles on breast and prostate cells. The catechol metabolite 4-hydroxyestradiol (4-OHE2) enhances cell proliferation, while 2-methoxyestradiol (2 ME) possesses anticancer activity. The major metabolizing enzyme responsible for detoxifying the deleterious metabolite 4-OHE2 and forming the anticancer metabolite 2 ME is Catechol-O-Methyl Transferase (COMT). The current work investigated the relationship between the expression level of COMT and the cell proliferation of hormone-responsive cancers. The results showed that COMT silencing enhanced the cell proliferation of ER-α positive cancer cells MCF-7 and PC-3 but not the cells that lack ER-α expression as MDA-MB231 and DU-145. The data generated from our study provides a better understanding of the effect of COMT on critical signaling pathways involved in the development and progression of breast cancer (BC) and prostate cancer (PC) including ER-α, p21, p27, NF-κB (P65) and CYP19A1. These findings suggest that COMT enzyme plays a tumor suppressor role in hormone receptor-positive tumors which opens the door for future studies to validate COMT expression as a novel biomarker for the prediction of cancer aggressiveness and treatment efficacy.
雌激素（E2）在激素反应性癌症的发展和进展中起着核心作用。雌激素代谢物对乳腺和前列腺细胞表现出刺激或抑制作用。儿茶酚代谢物 4-羟基雌二醇（4-OHE2）增强细胞增殖，而 2-甲氧基雌二醇（2-ME）具有抗癌活性。负责解毒有害代谢物 4-OHE2 并形成抗癌代谢物 2-ME 的主要代谢酶是儿茶酚-O-甲基转移酶（COMT）。目前的工作研究了 COMT 的表达水平与激素反应性癌症的细胞增殖之间的关系。结果表明，COMT 沉默增强了 ER-α 阳性癌细胞 MCF-7 和 PC-3 的细胞增殖，但对缺乏 ER-α 表达的细胞（如 MDA-MB231 和 DU-145）没有这种作用。我们的研究数据提供了对 COMT 对乳腺癌（BC）和前列腺癌（PC）发展和进展中涉及的关键信号通路的影响的更好理解，包括 ER-α、p21、p27、NF-κB（P65）和 CYP19A1。这些发现表明，COMT 酶在激素受体阳性肿瘤中发挥肿瘤抑制作用，为未来的研究打开了大门，以验证 COMT 表达作为预测癌症侵袭性和治疗效果的新型生物标志物。
