Department of Pharmacological and Pharmaceutical Sciences, College of Pharmacy, University of Houston, Houston, TX 77204, USA.
Drug Discovery Institute, University of Houston, Houston, TX 77204, USA.
Cells. 2020 May 9;9(5):1176. doi: 10.3390/cells9051176.
The tumor suppressor p53 is believed to be the mostly studied molecule in modern biomedical research. Although p53 interacts with hundreds of molecules to exert its biological functions, there are only a few modulators regulating its expression and function, with murine double minute 2 (MDM2) playing a key role in this regard. MDM2 also contributes to malignant transformation and cancer development through p53-dependent and -independent mechanisms. There is an increasing interest in developing MDM2 inhibitors for cancer prevention and therapy. We recently demonstrated that the nuclear factor of activated T cells 1 (NFAT1) activates MDM2 expression. NFAT1 regulates several cellular functions in cancer cells, such as cell proliferation, migration, invasion, angiogenesis, and drug resistance. Both NFAT isoforms and MDM2 are activated and overexpressed in several cancer subtypes. In addition, a positive correlation exists between NFAT1 and MDM2 in tumor tissues. Our recent clinical study has demonstrated that high expression levels of NFAT1 and MDM2 are independent predictors of a poor prognosis in patients with hepatocellular carcinoma. Thus, inhibition of the NFAT1-MDM2 pathway appears to be a novel potential therapeutic strategy for cancer. In this review, we summarize the potential oncogenic roles of MDM2 and NFAT1 in cancer cells and discuss the efforts of discovery and the development of several newly identified MDM2 and NFAT1 inhibitors, focusing on their potent in vitro and in vivo anticancer activities. This review also highlights strategies and future directions, including the need to focus on the development of more specific and effective NFAT1-MDM2 dual inhibitors for cancer therapy.
抑癌因子 p53 被认为是现代生物医学研究中研究最多的分子。尽管 p53 与数百种分子相互作用以发挥其生物学功能，但只有少数调节剂调节其表达和功能，其中鼠双微体 2（MDM2）在这方面起着关键作用。MDM2 还通过 p53 依赖和非依赖机制促进恶性转化和癌症发展。人们越来越有兴趣开发 MDM2 抑制剂用于癌症的预防和治疗。我们最近证明，激活 T 细胞的核因子 1（NFAT1）激活 MDM2 的表达。NFAT1 调节癌细胞中的几种细胞功能，如细胞增殖、迁移、侵袭、血管生成和耐药性。两种 NFAT 同工型和 MDM2 在几种癌症亚型中均被激活和过表达。此外，NFAT1 和 MDM2 在肿瘤组织中存在正相关。我们最近的临床研究表明，NFAT1 和 MDM2 的高表达水平是肝细胞癌患者预后不良的独立预测因子。因此，抑制 NFAT1-MDM2 途径似乎是癌症的一种新的潜在治疗策略。在这篇综述中，我们总结了 MDM2 和 NFAT1 在癌细胞中的潜在致癌作用，并讨论了发现和开发几种新鉴定的 MDM2 和 NFAT1 抑制剂的努力，重点介绍了它们在体外和体内的强大抗癌活性。这篇综述还强调了策略和未来方向，包括需要专注于开发更特异和有效的 NFAT1-MDM2 双重抑制剂用于癌症治疗。
