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Cells
Special Issues
The Role of MDM2 in Cancer Development and Prevention
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The Role of MDM2 in Cancer Development and Prevention

A special issue of Cells (ISSN 2073-4409). This special issue belongs to the section "Cellular Pathology".

Deadline for manuscript submissions: closed (1 June 2020) | Viewed by 12747

Special Issue Editor

Prof. Dr. Ruiwen Zhang

E-Mail Website
Guest Editor
College of Pharmacy, University of Houston, Houston, TX 77204-5037, USA
Interests: oncogene; tumor supressor; drug discovery and development; targeted therapy; cancer prevention
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

This year marks the 40th anniversary of the discovery of p53—a discovery that changed our understanding of cancer biology and cancer diagnosis and treatment! The p53 tumor suppressor, the mostly studied molecule thus far, is a key transcription factor regulating various cellular pathways such as DNA repair, cell cycle, apoptosis, angiogenesis, and senescence and often acts as an important defense mechanism against cancer onset and progression. One of the major discoveries in cancer biology is MDM2 as a major regulator of p53. The mdm2 gene was first identified as the gene responsible for the spontaneous transformation of an immortalized murine cell line, BALB/c 3T3, and has been subsequently confirmed as an oncogene, whose overexpression has been confirmed in many human cancers through various mechanisms, including gene amplification, single nucleotide polymorphism in its gene promoter, and increased transcription and translation. There is a p53–MDM2 feedback regulatory loop that is crucial for restricting p53 levels and activity during normal cell physiology and is tightly regulated by many factors. These co-factors alter MDM2 or p53 conformation, binding, localization, and expression and modulate the E3 ligase activity of MDM2 towards itself, p53, and other substrates, consequently regulating a variety of different cellular processes. Therefore, the inhibition of MDM2-p53 interaction presents an appealing therapeutic strategy for the treatment of cancer. There is a huge ongoing research effort in this field. Recent studies have revealed the MDM2-p53 interaction to be more complex than previously thought. Furthermore, MDM2 has extensive p53-independent activities. The MDM2 interactions with its partners provide a focal point for targeted therapy of cancer and other diseases. A number of the MDM2 inhibitors have entered clinical trials and have shown sufficient clinical efficacy. This Special Issue will cover a broad spectrum of MDM2 biology and therapeutic implications in cancer and other diseases. There will be more than dozen timely, comprehensive reviews and highly innovative original studies from leading groups in this field worldwide.  

Major Topics (more than one papers for each topic)

  • MDM2: Historic Perspective
  • The p53–MDM2 interaction and regulation
  • MDM2 and cancer: Basic biology
  • MDM2 and cancer: Clinical oncology
  • MDM2 interactive molecules: Beyond p53
  • MDM2 and diseases: Beyond cancer
  • MDM2 targeted therapy: Rational drug design, target validation, preclinical and clinical development

Prof. Ruiwen Zhang
Guest Editor

Manuscript Submission Information

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Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Cells is an international peer-reviewed open access semimonthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2700 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • MDM2
  • P53
  • MDMX
  • oncogene
  • tumor suppressor
  • cancer therapy
  • cancer metabolism

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Published Papers (3 papers)

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Research

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14 pages, 2768 KiB  
Article
Targeted Brain Tumor Therapy by Inhibiting the MDM2 Oncogene: In Vitro and In Vivo Antitumor Activity and Mechanism of Action
by Surendra R. Punganuru, Viswanath Arutla, Wei Zhao, Mehrdad Rajaei, Hemantkumar Deokar, Ruiwen Zhang, John K. Buolamwini, Kalkunte S. Srivenugopal and Wei Wang
Cells 2020, 9(7), 1592; https://doi.org/10.3390/cells9071592 - 1 Jul 2020
Cited by 13 | Viewed by 4023
Abstract
There is a desperate need for novel and efficacious chemotherapeutic strategies for human brain cancers. There are abundant molecular alterations along the p53 and MDM2 pathways in human glioma, which play critical roles in drug resistance. The present study was designed to evaluate [...] Read more.
There is a desperate need for novel and efficacious chemotherapeutic strategies for human brain cancers. There are abundant molecular alterations along the p53 and MDM2 pathways in human glioma, which play critical roles in drug resistance. The present study was designed to evaluate the in vitro and in vivo antitumor activity of a novel brain-penetrating small molecule MDM2 degrader, termed SP-141. In a panel of nine human glioblastoma and medulloblastoma cell lines, SP-141, as a single agent, potently killed the brain tumor-derived cell lines with IC50 values ranging from 35.8 to 688.8 nM. Treatment with SP-141 resulted in diminished MDM2 and increased p53 and p21cip1 levels, G2/M cell cycle arrest, and marked apoptosis. In intracranial xenograft models of U87MG glioblastoma (wt p53) and DAOY medulloblastoma (mutant p53) expressing luciferase, treatment with SP-141 caused a significant 4- to 9-fold decrease in tumor growth in the absence of discernible toxicity. Further, combination treatment with a low dose of SP-141 (IC20) and temozolomide, a standard anti-glioma drug, led to synergistic cell killing (1.3- to 31-fold) in glioma cell lines, suggesting a novel means for overcoming temozolomide resistance. Considering that SP-141 can be taken up by the brain without the need for any special delivery, our results suggest that SP-141 should be further explored for the treatment of tumors of the central nervous system, regardless of the p53 status of the tumor. Full article
(This article belongs to the Special Issue The Role of MDM2 in Cancer Development and Prevention)
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12 pages, 4109 KiB  
Article
Inhibition of Transglutaminase 2 but Not of MDM2 Has a Significant Therapeutic Effect on Renal Cell Carcinoma
by Joon Hee Kang, Seon-Hyeong Lee, Jae-Seon Lee, Su-Jin Oh, Ji Sun Ha, Hyun-Jung Choi and Soo-Youl Kim
Cells 2020, 9(6), 1475; https://doi.org/10.3390/cells9061475 - 16 Jun 2020
Cited by 5 | Viewed by 3194
Abstract
More than 50% of human cancers harbor TP53 mutations and increased expression of Mouse double minute 2 homolog (MDM2), which contribute to cancer progression and drug resistance. Renal cell carcinoma (RCC) has an unusually high incidence of wild-type p53, with a mutation [...] Read more.
More than 50% of human cancers harbor TP53 mutations and increased expression of Mouse double minute 2 homolog (MDM2), which contribute to cancer progression and drug resistance. Renal cell carcinoma (RCC) has an unusually high incidence of wild-type p53, with a mutation rate of less than 4%. MDM2 is master regulator of apoptosis in cancer cells, which is triggered through proteasomal degradation of wild-type p53. Recently, we found that p53 protein levels in RCC are regulated by autophagic degradation. Transglutaminase 2 (TGase 2) was responsible for p53 degradation through this pathway. Knocking down TGase 2 increased p53-mediated apoptosis in RCC. Therefore, we asked whether depleting p53 from RCC cells occurs via MDM2-mediated proteasomal degradation or via TGase 2-mediated autophagic degradation. In vitro gene knockdown experiments revealed that stability of p53 in RCC was inversely related to levels of both MDM2 and TGase 2 protein. Therefore, we examined the therapeutic efficacy of inhibitors of TGase 2 and MDM2 in an in vivo model of RCC. The results showed that inhibiting TGase 2 but not MDM2 had efficient anticancer effects. Full article
(This article belongs to the Special Issue The Role of MDM2 in Cancer Development and Prevention)
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Review

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15 pages, 1442 KiB  
Review
Two Birds with One Stone: NFAT1-MDM2 Dual Inhibitors for Cancer Therapy
by Wei Wang, Atif Zafar, Mehrdad Rajaei and Ruiwen Zhang
Cells 2020, 9(5), 1176; https://doi.org/10.3390/cells9051176 - 9 May 2020
Cited by 8 | Viewed by 4702
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 [...] Read more.
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. Full article
(This article belongs to the Special Issue The Role of MDM2 in Cancer Development and Prevention)
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