Abstract
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.
Highlights
Cancer remains a leading cause of death and poses a major public health challenge worldwide.Thanks to the impressive progresses made in basic, translational, and clinical biomedical research and development in past decades, we have witnessed a significant improvement in cancer diagnosis and treatment, especially in the fields of targeted therapy and immunotherapy as well as combination therapy with various therapeutic modality
murine double minute 2 (MDM2) was initially discovered as a negative regulator of p53 [8,9], but it has subsequently been demonstrated that the MDM2 oncoprotein interacts with many other molecules [5], such as E2 promoter binding factor 1 (E2F1)/retinoblastoma protein (Rb) and X-linked inhibitor of apoptosis protein (XIAP), allowing it to exert a variety of p53-independent effects [10,11]
P53-independent MDM2 inhibitors may have an implication in a broad spectrum of cancers
Summary
Cancer remains a leading cause of death and poses a major public health challenge worldwide. MDM2 was initially discovered as a negative regulator of p53 [8,9], but it has subsequently been demonstrated that the MDM2 oncoprotein interacts with many other molecules [5], such as E2 promoter binding factor 1 (E2F1)/retinoblastoma protein (Rb) and X-linked inhibitor of apoptosis protein (XIAP), allowing it to exert a variety of p53-independent effects [10,11] These characteristics make MDM2 a promising target for the development of anticancer therapies. Combinatorial library screening has identified several small molecules as MDM2 inhibitors, including spiroxindoles [25,26], nutlins [27,28], isolindones [5,29], and chalone [5,30] derivatives One such molecule, Nutlin, binds to MDM2 in the p53-binding pocket and activates p53 to induce cell cycle arrest and apoptosis in cancer cells [5,28,29,30]. This study suggests that a double targeting strategy may be a promising approach to improve the efficacy and safety of MDM2 inhibitors for cancer treatment of advanced pancreatic cancer
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