Two Birds with One Stone: NFAT1-MDM2 Dual Inhibitors for Cancer Therapy
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) playin...
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| Format: | Article |
| Language: | English |
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MDPI AG
2020-05-01
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| Series: | Cells |
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| Online Access: | https://www.mdpi.com/2073-4409/9/5/1176 |
| _version_ | 1797568489835200512 |
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| author | Wei Wang Atif Zafar Mehrdad Rajaei Ruiwen Zhang |
| author_facet | Wei Wang Atif Zafar Mehrdad Rajaei Ruiwen Zhang |
| author_sort | Wei Wang |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-03-10T19:57:37Z |
| format | Article |
| id | doaj.art-9a0b7a77760448f7b7e8f6a16f16bb49 |
| institution | Directory Open Access Journal |
| issn | 2073-4409 |
| language | English |
| last_indexed | 2024-03-10T19:57:37Z |
| publishDate | 2020-05-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Cells |
| spelling | doaj.art-9a0b7a77760448f7b7e8f6a16f16bb492023-11-19T23:52:31ZengMDPI AGCells2073-44092020-05-0195117610.3390/cells9051176Two Birds with One Stone: NFAT1-MDM2 Dual Inhibitors for Cancer TherapyWei Wang0Atif Zafar1Mehrdad Rajaei2Ruiwen Zhang3Department of Pharmacological and Pharmaceutical Sciences, College of Pharmacy, University of Houston, Houston, TX 77204, USADepartment of Pharmacological and Pharmaceutical Sciences, College of Pharmacy, University of Houston, Houston, TX 77204, USADepartment of Pharmacological and Pharmaceutical Sciences, College of Pharmacy, University of Houston, Houston, TX 77204, USADepartment of Pharmacological and Pharmaceutical Sciences, College of Pharmacy, University of Houston, Houston, TX 77204, USAThe 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.https://www.mdpi.com/2073-4409/9/5/1176NFAT1MDM2p53dual inhibitorscancer therapy |
| spellingShingle | Wei Wang Atif Zafar Mehrdad Rajaei Ruiwen Zhang Two Birds with One Stone: NFAT1-MDM2 Dual Inhibitors for Cancer Therapy Cells NFAT1 MDM2 p53 dual inhibitors cancer therapy |
| title | Two Birds with One Stone: NFAT1-MDM2 Dual Inhibitors for Cancer Therapy |
| title_full | Two Birds with One Stone: NFAT1-MDM2 Dual Inhibitors for Cancer Therapy |
| title_fullStr | Two Birds with One Stone: NFAT1-MDM2 Dual Inhibitors for Cancer Therapy |
| title_full_unstemmed | Two Birds with One Stone: NFAT1-MDM2 Dual Inhibitors for Cancer Therapy |
| title_short | Two Birds with One Stone: NFAT1-MDM2 Dual Inhibitors for Cancer Therapy |
| title_sort | two birds with one stone nfat1 mdm2 dual inhibitors for cancer therapy |
| topic | NFAT1 MDM2 p53 dual inhibitors cancer therapy |
| url | https://www.mdpi.com/2073-4409/9/5/1176 |
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