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Wang W, Du Y, Datta S, Fowler JF, Sang HT, Albadari N, Li W, Foster J, Zhang R. Targeting the MYCN-MDM2 pathways for cancer therapy: Are they druggable? Genes Dis 2025; 12:101156. [PMID: 39802403 PMCID: PMC11719324 DOI: 10.1016/j.gendis.2023.101156] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/15/2023] [Revised: 09/11/2023] [Accepted: 09/26/2023] [Indexed: 01/16/2025] Open
Abstract
Targeting oncogenes and their interactive partners is an effective approach to developing novel targeted therapies for cancer and other chronic diseases. We and others have long suggested the MDM2 oncogene being an excellent target for cancer therapy, based on its p53-dependent and -independent oncogenic activities in a variety of cancers. The MYC family proteins are transcription factors that also regulate diverse biological functions. Dysregulation of MYC, such as amplification of MYCN, is associated with tumorigenesis, especially for neuroblastoma. Although the general survival rate of neuroblastoma patients has significantly improved over the past few decades, high-risk neuroblastoma still presents a poor prognosis. Therefore, innovative and more potent therapeutic strategies are needed to eradicate these aggressive neoplasms. This review focuses on the oncogenic properties of MYCN and its molecular regulation and summarizes the major therapeutic strategies being developed based on preclinical findings. We also highlight the potential benefits of targeting both the MYCN and MDM2 oncogenes, providing preclinical evidence of the efficacy and safety of this approach. In conclusion, the development of effective small molecules that inhibit both MYCN and MDM2 represents a promising new strategy for the treatment of neuroblastoma and other cancers.
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Affiliation(s)
- Wei Wang
- 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
| | - Yi Du
- Department of Pharmacological and Pharmaceutical Sciences, College of Pharmacy, University of Houston, Houston, TX 77204, USA
| | - Sayantap Datta
- Department of Pharmacological and Pharmaceutical Sciences, College of Pharmacy, University of Houston, Houston, TX 77204, USA
| | - Josef F. Fowler
- Department of Pharmacological and Pharmaceutical Sciences, College of Pharmacy, University of Houston, Houston, TX 77204, USA
| | - Hannah T. Sang
- Department of Pharmacological and Pharmaceutical Sciences, College of Pharmacy, University of Houston, Houston, TX 77204, USA
| | - Najah Albadari
- College of Pharmacy, The University of Tennessee Health Science Center, Memphis, TN 38163, USA
| | - Wei Li
- College of Pharmacy, The University of Tennessee Health Science Center, Memphis, TN 38163, USA
| | - Jennifer Foster
- Texas Children's Hospital, Department of Pediatrics, Section of Hematology-Oncology Baylor College of Medicine, Houston, TX 77030, USA
| | - Ruiwen Zhang
- 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
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Aptullahoglu E, Howladar M, Wallis JP, Marr H, Marshall S, Irving J, Willmore E, Lunec J. Targeting the MDM2-p53 Interaction with Siremadlin: A Promising Therapeutic Strategy for Treating TP53 Wild-Type Chronic Lymphocytic Leukemia. Cancers (Basel) 2025; 17:274. [PMID: 39858058 PMCID: PMC11763703 DOI: 10.3390/cancers17020274] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/12/2024] [Revised: 01/09/2025] [Accepted: 01/09/2025] [Indexed: 01/27/2025] Open
Abstract
Background: Chronic lymphocytic leukemia (CLL) treatment has transitioned from traditional chemotherapy to more targeted therapies, but challenges such as resistance and suboptimal responses persist. This study aimed to evaluate HDM201, a second-generation MDM2-p53 binding antagonist, as a novel therapeutic strategy for CLL, with a focus on its effectiveness across different TP53 genetic contexts. Methods: We utilized a panel of B cell leukemia-derived cell lines with varying TP53 statuses, including TP53-knockout (KO) derivatives of the human B cell line Nalm-6, and assessed the impact of HDM201 on primary CLL samples with both TP53 wild-type and mutant backgrounds. Results: Our results revealed that TP53 wild-type and heterozygous TP53-KO Nalm-6 cells were sensitive to HDM201, whereas homozygous TP53-KO cells and B cells with TP53 mutations exhibited significant resistance. Resistance was also noted in primary CLL samples with TP53 mutations. HDM201 effectively stabilized p53 and induced apoptosis in TP53 wild-type cells but had limited efficacy in TP53 mutant cells. Conclusions: These findings indicate that HDM201 holds promise as an additional targeted therapy option for wild-type TP53 CLL. The results underline the importance of TP53 status in predicting treatment efficacy and highlight the potential of HDM201 as a valuable addition to explore in CLL therapy. Future research should focus on identifying additional biomarkers of response and exploring the optimal way to include HDM201 in combination therapies to improve treatment outcomes in CLL.
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Affiliation(s)
- Erhan Aptullahoglu
- Biosciences Institute & Newcastle University Cancer Centre, Medical Faculty, Newcastle University, Newcastle upon Tyne NE2 4HH, UK; (E.A.); (M.H.); (J.I.); (E.W.)
- Department of Molecular Biology and Genetics, Faculty of Science, Bilecik Şeyh Edebali University, 11100 Bilecik, Türkiye
| | - Mohammed Howladar
- Biosciences Institute & Newcastle University Cancer Centre, Medical Faculty, Newcastle University, Newcastle upon Tyne NE2 4HH, UK; (E.A.); (M.H.); (J.I.); (E.W.)
| | - Jonathan P. Wallis
- Department of Haematology, Freeman Hospital, Newcastle upon Tyne NHS Foundation Trust, Newcastle upon Tyne NE7 7DN, UK
| | - Helen Marr
- Department of Haematology, Freeman Hospital, Newcastle upon Tyne NHS Foundation Trust, Newcastle upon Tyne NE7 7DN, UK
| | - Scott Marshall
- Department of Haematology, City Hospitals Sunderland NHS Trust, Sunderland SR4 7TP, UK
| | - Julie Irving
- Biosciences Institute & Newcastle University Cancer Centre, Medical Faculty, Newcastle University, Newcastle upon Tyne NE2 4HH, UK; (E.A.); (M.H.); (J.I.); (E.W.)
| | - Elaine Willmore
- Biosciences Institute & Newcastle University Cancer Centre, Medical Faculty, Newcastle University, Newcastle upon Tyne NE2 4HH, UK; (E.A.); (M.H.); (J.I.); (E.W.)
| | - John Lunec
- Biosciences Institute & Newcastle University Cancer Centre, Medical Faculty, Newcastle University, Newcastle upon Tyne NE2 4HH, UK; (E.A.); (M.H.); (J.I.); (E.W.)
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Mai Y, Jing Z, Sun P, Wang Y, Dong P, Liu J. TARDBP drives T-cell acute lymphoblastic leukemia progression by binding MDM2 mRNA, involving β-catenin pathway. FASEB J 2024; 38:e70110. [PMID: 39417407 DOI: 10.1096/fj.202400557rr] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/12/2024] [Revised: 09/27/2024] [Accepted: 10/03/2024] [Indexed: 10/19/2024]
Abstract
T-cell acute lymphoblastic leukemia (T-ALL) is a dangerous hematological malignancy. The trans-activation response DNA binding protein (TARDBP), an RNA/DNA binding protein, is involved in the growth and metastasis of multiple cancers. However, TARDBP has not been reported in T-ALL. It was found that TARDBP was highly expressed in pediatric T-ALL samples by microarray GSE26713 (log2 fold change >1, p < .05). Herein, TARDBP was silenced and overexpressed by lentivirus transduction in T-ALL cell lines, including Jurkat and Molt4 cells. In vitro, silencing TARDBP inhibited T-ALL cell proliferation and cycle progression and accelerated cell apoptosis, while overexpressing TARDBP induced the opposite effects. In addition, we investigated whether the β-catenin pathway could be activated by TARDBP in T-ALL cells. Moreover, XAV-939, a β-catenin inhibitor, was capable of suppressing the malignant phenotypes in TARDBP-overexpressed T-ALL cells. In vivo, TARDBP-silenced or TARDBP-overexpressed T-ALL cells were injected into mice. We found that TARDBP promoted T-ALL cell growth in the spleens and bone marrows of mice. On the basis of GSE26713, there was a significant correlation between TARDBP and mouse double minute 2 (MDM2). The RIP-PCR assay demonstrated that TARDBP bound MDM2 mRNA in T-ALL cells. The rescue experiments further revealed the roles of the TARDBP/MDM2 axis in T-ALL cell phenotypes, which was also reflected by mRNA-seq. In aggregate, we explored a promising biomarker, TARDBP, for T-ALL treatment. The underlying mechanisms might involve the interaction with MDM2 mRNA and the regulation of the β-catenin pathway.
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Affiliation(s)
- Yumiao Mai
- Department of Pediatrics, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China
| | - Zhaohe Jing
- Department of Pediatrics, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China
| | - Pan Sun
- Department of Pediatrics, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China
| | - Yingjie Wang
- Department of Pediatrics, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China
| | - Pengpeng Dong
- Department of Pediatrics, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China
| | - Jian Liu
- Department of Pediatrics, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China
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Cui J, Wang Q, Li M. Xinnaotongluo liquid protects H9c2 cells from H/R-induced damage by regulating MDM2/STEAP3. PLoS One 2024; 19:e0302407. [PMID: 38640125 PMCID: PMC11029650 DOI: 10.1371/journal.pone.0302407] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/31/2024] [Accepted: 04/01/2024] [Indexed: 04/21/2024] Open
Abstract
Xinnaotongluo liquid has been used to improve the clinical symptoms of patients with myocardial infarction. However, the molecular mechanism of Xinnaotongluo liquid is not completely understood. H9c2 cells exposed to hypoxia/reoxygenation (H/R) was used to simulate damage to cardiomyocytes in myocardial infarction in vitro. The biological indicators of H9c2 cells were measured by cell counting kit-8, enzyme linked immunoabsorbent assay, and western blot assay. In H/R-induced H9c2 cells, a markedly reduced murine double minute 2 (MDM2) was observed. However, the addition of Xinnaotongluo liquid increased MDM2 expression in H/R-induced H9c2 cells. And MDM2 overexpression strengthened the beneficial effects of Xinnaotongluo liquid on H9c2 cells from the perspective of alleviating oxidative damage, cellular inflammation, apoptosis and ferroptosis of H/R-induced H9c2 cells. Moreover, MDM2 overexpression reduced the protein expression of p53 and Six-Transmembrane Epithelial Antigen of Prostate 3 (STEAP3). Whereas, STEAP3 overexpression hindered the function of MDM2-overexpression in H/R-induced H9c2 cells. Our results insinuated that Xinnaotongluo liquid could protect H9c2 cells from H/R-induced damage by regulating MDM2/STEAP3, which provide a potential theoretical basis for further explaining the working mechanism of Xinnaotongluo liquid.
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Affiliation(s)
- Jiankun Cui
- Department of Cardiology, The First Affiliated Hospital of Heilongjiang University of Chinese Medicine, Harbin, 150040, Heilongjiang, P. R. China
| | - Qinwen Wang
- Out-Patient Department, Beijing Garrison District Haidian Retired Cadres Twenty-Sixth, Beijing Garrison District Haidian Retired Cadres Twenty-Sixth, Beijing, China
| | - Minghao Li
- Department of Cardiology, Beidahuang Group General Hospital, Harbin, 150088, Heilongjiang, P. R. China
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Albadari N, Xie Y, Liu T, Wang R, Gu L, Zhou M, Wu Z, Li W. Synthesis and biological evaluation of dual MDM2/XIAP inhibitors based on the tetrahydroquinoline scaffold. Eur J Med Chem 2023; 255:115423. [PMID: 37130471 PMCID: PMC10246915 DOI: 10.1016/j.ejmech.2023.115423] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/15/2022] [Revised: 04/20/2023] [Accepted: 04/26/2023] [Indexed: 05/04/2023]
Abstract
Overexpression of both human murine double minute 2 (MDM2) and X-linked inhibitor of apoptosis protein (XIAP) is detected in tumor cells from several cancer types, including childhood acute leukemia lymphoma (ALL), neuroblastoma (NB), and prostate cancer, and is associated with disease progression and treatment resistance. In this report, we described the design and syntheses of a series of dual MDM2/XIAP inhibitors based on the tetrahydroquinoline scaffold from our previously reported lead compound JW-2-107 and tested their cytotoxicity in a panel of human cancer cell lines. The best compound identified in this study is compound 3e. Western blot analyses demonstrated that treatments with 3e decreased MDM2 and XIAP protein levels and increased expression of p53, resulting in cancer cell growth inhibition and cell death. Furthermore, compound 3e effectively inhibited tumor growth in vivo when tested using a human 22Rv1 prostate cancer xenograft model. Collectively, results in this study strongly suggest that the tetrahydroquinoline scaffold, represented by 3e and our earlier lead compound JW-2-107, has abilities to dual target MDM2 and XIAP and is promising for further preclinical development.
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Affiliation(s)
- Najah Albadari
- Department of Pharmaceutical Sciences, College of Pharmacy, University of Tennessee Health Science Center, Memphis, TN, 38163, United States
| | - Yang Xie
- Department of Pharmaceutical Sciences, College of Pharmacy, University of Tennessee Health Science Center, Memphis, TN, 38163, United States
| | - Tao Liu
- Department of Pediatrics and Aflac Cancer and Blood Disorders Center, Emory University School of Medicine, Atlanta, GA, 30322, United States
| | - Rui Wang
- Department of Pharmaceutical Sciences, College of Pharmacy, University of Tennessee Health Science Center, Memphis, TN, 38163, United States
| | - Lubing Gu
- Department of Pediatrics and Aflac Cancer and Blood Disorders Center, Emory University School of Medicine, Atlanta, GA, 30322, United States
| | - Muxiang Zhou
- Department of Pediatrics and Aflac Cancer and Blood Disorders Center, Emory University School of Medicine, Atlanta, GA, 30322, United States.
| | - Zhongzhi Wu
- Department of Pharmaceutical Sciences, College of Pharmacy, University of Tennessee Health Science Center, Memphis, TN, 38163, United States.
| | - Wei Li
- Department of Pharmaceutical Sciences, College of Pharmacy, University of Tennessee Health Science Center, Memphis, TN, 38163, United States.
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Choudhary HB, Mandlik SK, Mandlik DS. Role of p53 suppression in the pathogenesis of hepatocellular carcinoma. World J Gastrointest Pathophysiol 2023; 14:46-70. [PMID: 37304923 PMCID: PMC10251250 DOI: 10.4291/wjgp.v14.i3.46] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/27/2023] [Revised: 05/19/2023] [Accepted: 05/31/2023] [Indexed: 06/01/2023] Open
Abstract
In the world, hepatocellular carcinoma (HCC) is among the top 10 most prevalent malignancies. HCC formation has indeed been linked to numerous etiological factors, including alcohol usage, hepatitis viruses and liver cirrhosis. Among the most prevalent defects in a wide range of tumours, notably HCC, is the silencing of the p53 tumour suppressor gene. The control of the cell cycle and the preservation of gene function are both critically important functions of p53. In order to pinpoint the core mechanisms of HCC and find more efficient treatments, molecular research employing HCC tissues has been the main focus. Stimulated p53 triggers necessary reactions that achieve cell cycle arrest, genetic stability, DNA repair and the elimination of DNA-damaged cells’ responses to biological stressors (like oncogenes or DNA damage). To the contrary hand, the oncogene protein of the murine double minute 2 (MDM2) is a significant biological inhibitor of p53. MDM2 causes p53 protein degradation, which in turn adversely controls p53 function. Despite carrying wt-p53, the majority of HCCs show abnormalities in the p53-expressed apoptotic pathway. High p53 in-vivo expression might have two clinical impacts on HCC: (1) Increased levels of exogenous p53 protein cause tumour cells to undergo apoptosis by preventing cell growth through a number of biological pathways; and (2) Exogenous p53 makes HCC susceptible to various anticancer drugs. This review describes the functions and primary mechanisms of p53 in pathological mechanism, chemoresistance and therapeutic mechanisms of HCC.
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Affiliation(s)
- Heena B Choudhary
- Department of Pharmacology, BVDU, Poona College of Pharmacy, Pune 411038, Maharashtra, India
| | - Satish K Mandlik
- Department of Pharmaceutics, BVDU, Poona College of Pharmacy, Pune 411038, Maharashtra, India
| | - Deepa S Mandlik
- Department of Pharmacology, BVDU, Poona College of Pharmacy, Pune 411038, Maharashtra, India
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Sun SY, Crago A. MDM2 Implications for Potential Molecular Pathogenic Therapies of Soft-Tissue Tumors. J Clin Med 2023; 12:3638. [PMID: 37297833 PMCID: PMC10253559 DOI: 10.3390/jcm12113638] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/26/2023] [Revised: 04/14/2023] [Accepted: 05/03/2023] [Indexed: 06/12/2023] Open
Abstract
Murine double minute 2 (MDM2, gene name MDM2) is an oncogene that mainly codes for a protein that acts as an E3 ubiquitin ligase, which targets the tumor suppressor protein p53 for degradation. Overexpression of MDM2 regulates the p53 protein levels by binding to it and promoting its degradation by the 26S proteasome. This leads to the inhibition of p53's ability to regulate cell cycle progression and apoptosis, allowing for uncontrolled cell growth, and can contribute to the development of soft-tissue tumors. The application of cellular stress leads to changes in the binding of MDM2 to p53, which prevents MDM2 from degrading p53. This results in an increase in p53 levels, which triggers either cell cycle arrest or apoptosis. Inhibiting the function of MDM2 has been identified as a potential therapeutic strategy for treating these types of tumors. By blocking the activity of MDM2, p53 function can be restored, potentially leading to tumor cell death and inhibiting the growth of tumors. However, further research is needed to fully understand the implications of MDM2 inhibition for the treatment of soft-tissue tumors and to determine the safety and efficacy of these therapies in clinical trials. An overview of key milestones and potential uses of MDM2 research is presented in this review.
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Affiliation(s)
- Sylvia Yao Sun
- Sarcoma Biology Laboratory, Department of Surgery, Memorial Sloan Kettering Cancer Center, 417 E 618 St, New York, NY 10065, USA
| | - Aimee Crago
- Gastric and Mixed Tumor Service, Department of Surgery, Memorial Sloan Kettering Cancer Center, 1275 York Avenue, New York, NY 10065, USA
- Department of Surgery, Weill Cornell Medical Center, 525 E 68th St M 404, New York, NY 10065, USA
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Menon AA, Deshpande V, Suster D. MDM2 for the practicing pathologist: a primer. J Clin Pathol 2023; 76:285-290. [PMID: 36898827 DOI: 10.1136/jcp-2022-208687] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 02/22/2023] [Indexed: 03/12/2023]
Abstract
The mouse double minute 2 (MDM2) gene is located on the long arm of chromosome 12 and is the primary negative regulator of p53. The MDM2 gene encodes an E3 ubiquitin-protein ligase that mediates the ubiquitination of p53, leading to its degradation. MDM2 enhances tumour formation by inactivating the p53 tumour suppressor protein. The MDM2 gene also has many p53-independent functions. Alterations of MDM2 may occur through various mechanisms and contribute to the pathogenesis of many human tumours and some non-neoplastic diseases. Detection of MDM2 amplification is used in the clinical practice setting to help diagnose multiple tumour types, including lipomatous neoplasms, low-grade osteosarcomas and intimal sarcoma, among others. It is generally a marker of adverse prognosis, and MDM2-targeted therapies are currently in clinical trials. This article provides a concise overview of the MDM2 gene and discusses practical diagnostic applications pertaining to human tumour biology.
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Affiliation(s)
- Aswathy Ashok Menon
- Department of Pathology, Neuberg Anand Reference Laboratory, Bengaluru, Karnataka, India
| | - Vikram Deshpande
- Department of Pathology, Massachusetts General Hospital, Boston, Massachusetts, USA
| | - David Suster
- Department of Pathology, Rutgers University New Jersey Medical School, Newark, New Jersey, USA
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Zhang A, Yang Y, Zeng L, Zhao Z, Zhou Y, Yang Z, Liao Q, Xiao S, Ma H, Li J, Mao F, Qin Y, Zhang Y, Zhang Y, Yu Z, Xiang Z. MDM2 is involved in the regulation of p53 expression in the immune response of oyster Crassostrea hongkongensis. DEVELOPMENTAL AND COMPARATIVE IMMUNOLOGY 2022; 128:104321. [PMID: 34798199 DOI: 10.1016/j.dci.2021.104321] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 08/27/2021] [Revised: 11/10/2021] [Accepted: 11/12/2021] [Indexed: 06/13/2023]
Abstract
MDM2 (mouse double-minute) and p53 form a negative feedback loop and play a prominent role in preventing the induction of uncontrolled apoptosis. To better understand their potential roles in oyster Crassostrea hongkongensis, MDM2 and p53 homologs were first isolated and cloned in C. hongkongensis (named ChMDM2 and Chp53), and their mRNA expression patterns in tissues and developmental stages were analyzed. Multiple sequence alignment analysis and phylogenetic analysis of ChMDM2 and Chp53 displayed a high degree of homology and conservation. In addition, exposure to Vibrio coralliilyticus resulted in DNA damage and apoptosis in the hemocytes of C. hongkongensis, and found that the mRNA expression level of ChMDM2 was decreased, while the relative expression of Chp53 was significantly increased in the hemocytes and gills. Furthermore, fluorescence from ChMDM2-EGFP and Chp53-Red were found to be distributed in the nucleus of HEK293T cells. Besides, dual-luciferase reporter assays showed that ChMDM2 antagonized with Chp53 and participates in p53 signaling pathway. In addition, the interaction between ChMDM2 and Chp53 was confirmed strongly by Co-immunoprecipitation assays. Furthermore, the results of RNAi showed that ChMDM2 and Chp53 participated in apoptosis which induced infection of V. coralliilyticus. Taken together, our results characterized the features of ChMDM2 and Chp53, which played a critical role in apoptosis of C. hongkongensis.
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Affiliation(s)
- Aijiao Zhang
- Key Laboratory of Tropical Marine Bio-resources and Ecology, Guangdong Provincial Key Laboratory of Applied Marine Biology, South China Sea Institute of Oceanology, Chinese Academy of Science, Guangzhou, 510301, China; University of Chinese Academy of Sciences, Beijing, 100049, China
| | - Yucheng Yang
- Key Laboratory of Tropical Marine Bio-resources and Ecology, Guangdong Provincial Key Laboratory of Applied Marine Biology, South China Sea Institute of Oceanology, Chinese Academy of Science, Guangzhou, 510301, China; University of Chinese Academy of Sciences, Beijing, 100049, China
| | - Liang Zeng
- Key Laboratory of Tropical Marine Bio-resources and Ecology, Guangdong Provincial Key Laboratory of Applied Marine Biology, South China Sea Institute of Oceanology, Chinese Academy of Science, Guangzhou, 510301, China; University of Chinese Academy of Sciences, Beijing, 100049, China
| | - Zehui Zhao
- Key Laboratory of Tropical Marine Bio-resources and Ecology, Guangdong Provincial Key Laboratory of Applied Marine Biology, South China Sea Institute of Oceanology, Chinese Academy of Science, Guangzhou, 510301, China; University of Chinese Academy of Sciences, Beijing, 100049, China
| | - Yinyin Zhou
- Key Laboratory of Tropical Marine Bio-resources and Ecology, Guangdong Provincial Key Laboratory of Applied Marine Biology, South China Sea Institute of Oceanology, Chinese Academy of Science, Guangzhou, 510301, China; University of Chinese Academy of Sciences, Beijing, 100049, China
| | - Zhuo Yang
- Key Laboratory of Tropical Marine Bio-resources and Ecology, Guangdong Provincial Key Laboratory of Applied Marine Biology, South China Sea Institute of Oceanology, Chinese Academy of Science, Guangzhou, 510301, China; University of Chinese Academy of Sciences, Beijing, 100049, China
| | - Qingliang Liao
- Key Laboratory of Tropical Marine Bio-resources and Ecology, Guangdong Provincial Key Laboratory of Applied Marine Biology, South China Sea Institute of Oceanology, Chinese Academy of Science, Guangzhou, 510301, China; University of Chinese Academy of Sciences, Beijing, 100049, China
| | - Shu Xiao
- Key Laboratory of Tropical Marine Bio-resources and Ecology, Guangdong Provincial Key Laboratory of Applied Marine Biology, South China Sea Institute of Oceanology, Chinese Academy of Science, Guangzhou, 510301, China; Innovation Academy of South China Sea Ecology and Environmental Engineering (ISEE), Chinese Academy of Sciences, China
| | - Haitao Ma
- Key Laboratory of Tropical Marine Bio-resources and Ecology, Guangdong Provincial Key Laboratory of Applied Marine Biology, South China Sea Institute of Oceanology, Chinese Academy of Science, Guangzhou, 510301, China; Innovation Academy of South China Sea Ecology and Environmental Engineering (ISEE), Chinese Academy of Sciences, China
| | - Jun Li
- Key Laboratory of Tropical Marine Bio-resources and Ecology, Guangdong Provincial Key Laboratory of Applied Marine Biology, South China Sea Institute of Oceanology, Chinese Academy of Science, Guangzhou, 510301, China; Innovation Academy of South China Sea Ecology and Environmental Engineering (ISEE), Chinese Academy of Sciences, China
| | - Fan Mao
- Key Laboratory of Tropical Marine Bio-resources and Ecology, Guangdong Provincial Key Laboratory of Applied Marine Biology, South China Sea Institute of Oceanology, Chinese Academy of Science, Guangzhou, 510301, China; Innovation Academy of South China Sea Ecology and Environmental Engineering (ISEE), Chinese Academy of Sciences, China
| | - Yanping Qin
- Key Laboratory of Tropical Marine Bio-resources and Ecology, Guangdong Provincial Key Laboratory of Applied Marine Biology, South China Sea Institute of Oceanology, Chinese Academy of Science, Guangzhou, 510301, China; Innovation Academy of South China Sea Ecology and Environmental Engineering (ISEE), Chinese Academy of Sciences, China
| | - Yuehuan Zhang
- Key Laboratory of Tropical Marine Bio-resources and Ecology, Guangdong Provincial Key Laboratory of Applied Marine Biology, South China Sea Institute of Oceanology, Chinese Academy of Science, Guangzhou, 510301, China; Innovation Academy of South China Sea Ecology and Environmental Engineering (ISEE), Chinese Academy of Sciences, China
| | - Yang Zhang
- Key Laboratory of Tropical Marine Bio-resources and Ecology, Guangdong Provincial Key Laboratory of Applied Marine Biology, South China Sea Institute of Oceanology, Chinese Academy of Science, Guangzhou, 510301, China; Innovation Academy of South China Sea Ecology and Environmental Engineering (ISEE), Chinese Academy of Sciences, China
| | - Ziniu Yu
- Key Laboratory of Tropical Marine Bio-resources and Ecology, Guangdong Provincial Key Laboratory of Applied Marine Biology, South China Sea Institute of Oceanology, Chinese Academy of Science, Guangzhou, 510301, China; Innovation Academy of South China Sea Ecology and Environmental Engineering (ISEE), Chinese Academy of Sciences, China.
| | - Zhiming Xiang
- Key Laboratory of Tropical Marine Bio-resources and Ecology, Guangdong Provincial Key Laboratory of Applied Marine Biology, South China Sea Institute of Oceanology, Chinese Academy of Science, Guangzhou, 510301, China; Innovation Academy of South China Sea Ecology and Environmental Engineering (ISEE), Chinese Academy of Sciences, China.
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E3 ligases: a potential multi-drug target for different types of cancers and neurological disorders. Future Med Chem 2022; 14:187-201. [DOI: 10.4155/fmc-2021-0157] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022] Open
Abstract
Ubiquitylation is a posttranslational modification of proteins that is necessary for a variety of cellular processes. E1 ubiquitin activating enzyme, E2 ubiquitin conjugating enzyme, and E3 ubiquitin ligase are all involved in transferring ubiquitin to the target substrate to regulate cellular function. The objective of this review is to provide an overview of different aspects of E3 ubiquitin ligases that can lead to major biological system failure in several deadly diseases. The first part of this review covers the important characteristics of E3 ubiquitin ligases and their classification based on structural domains. Further, the authors provide some online resources that help researchers explore the data relevant to the enzyme. The following section delves into the involvement of E3 ubiquitin ligases in various diseases and biological processes, including different types of cancer and neurological disorders.
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Mödlhammer A, Pfurtscheller S, Feichtner A, Hartl M, Schneider R. The Diarylheptanoid Curcumin Induces MYC Inhibition and Cross-Links This Oncoprotein to the Coactivator TRRAP. Front Oncol 2021; 11:660481. [PMID: 33937075 PMCID: PMC8082493 DOI: 10.3389/fonc.2021.660481] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/29/2021] [Accepted: 03/23/2021] [Indexed: 11/13/2022] Open
Abstract
The c-Myc protein (MYC) is a transcription factor with strong oncogenic potential controlling fundamental cellular processes. In most human tumors, MYC is overexpressed by enhanced transcriptional activation, gene amplification, chromosomal rearrangements, or increased protein stabilization. To pharmacologically suppress oncogenic MYC functions, multiple approaches have been applied either to inhibit transcriptional activation of the endogenous MYC gene, or to interfere with biochemical functions of aberrantly activated MYC. Other critical points of attack are targeted protein modification, or destabilization leading to a non-functional MYC oncoprotein. It has been claimed that the natural compound curcumin representing the principal curcumoid of turmeric (Curcuma longa) has anticancer properties although its specificity, efficacy, and the underlying molecular mechanisms have been controversially discussed. Here, we have tested curcumin’s effect on MYC-dependent cell transformation and transcriptional activation, and found that this natural compound interferes with both of these MYC activities. Furthermore, in curcumin-treated cells, the endogenous 60-kDa MYC protein is covalently and specifically cross-linked to one of its transcriptional interaction partners, namely the 434-kDa transformation/transcription domain associated protein (TRRAP). Thereby, endogenous MYC levels are strongly reduced and cells stop to proliferate. TRRAP is a multidomain adaptor protein of the phosphoinositide 3-kinase-related kinases (PIKK) family and represents an important component of many histone acetyltransferase (HAT) complexes. TRRAP is important to mediate transcriptional activation executed by the MYC oncoprotein, but on the other hand TRRAP also negatively regulates protein stability of the tumor suppressor p53 (TP53). Curcumin-mediated covalent binding of MYC to TRRAP reduces the protein amounts of both interaction partners but does not downregulate TP53, so that the growth-arresting effect of wild type TP53 could prevail. Our results elucidate a molecular mechanism of curcumin action that specifically and irreversibly targets two crucial multifunctional cellular players. With regard to their broad impact in cancer, our findings contribute to explain the pleiotropic functions of curcumin, and suggest that this natural spice, or more bioavailable derivatives thereof, may constitute useful adjuvants in the therapy of MYC-dependent and TRRAP-associated human tumors.
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Affiliation(s)
- Alexander Mödlhammer
- Institute of Biochemistry and Center for Molecular Biosciences Innsbruck (CMBI), University of Innsbruck, Innsbruck, Austria
| | - Sandra Pfurtscheller
- Institute of Biochemistry and Center for Molecular Biosciences Innsbruck (CMBI), University of Innsbruck, Innsbruck, Austria
| | - Andreas Feichtner
- Institute of Biochemistry and Center for Molecular Biosciences Innsbruck (CMBI), University of Innsbruck, Innsbruck, Austria
| | - Markus Hartl
- Institute of Biochemistry and Center for Molecular Biosciences Innsbruck (CMBI), University of Innsbruck, Innsbruck, Austria
| | - Rainer Schneider
- Institute of Biochemistry and Center for Molecular Biosciences Innsbruck (CMBI), University of Innsbruck, Innsbruck, Austria
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12
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Dowarha D, Chou RH, Yu C. S100A1 blocks the interaction between p53 and mdm2 and decreases cell proliferation activity. PLoS One 2020; 15:e0234152. [PMID: 32497081 PMCID: PMC7272100 DOI: 10.1371/journal.pone.0234152] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/25/2020] [Accepted: 05/19/2020] [Indexed: 01/10/2023] Open
Abstract
About 50% of human cancers across the globe arise due to a mutation in the p53 gene which gives rise to its functional inactive form, and in the rest of the cancer the efficacy of active p53 (wild-type) is hindered by MDM2-mediated degradation. Breakdown of the p53-MDM2 association may constitute an effective strategy to stimulate or reinstate the activity of wild type p53, thereby reviving the p53 tumor suppressor capability. S100A1 has been revealed to associate with the N-terminal domain of MDM2 and p53 protein. We utilized NMR spectroscopy to study the interface amongst the S100A1 and N-terminal domain of MDM2. Additionally, the S100A1-MDM2 complex generated through the HADDOCK program was then superimposed with the p53 (peptide) -MDM2 complex reported earlier. The overlay indicated that a segment of S100A1 could block the interaction of p53 (peptide) -MDM2 complex significantly. To further justify our assumption, we performed HSQC-NMR titration for the S100A1 and p53 N-terminal domain (p53-TAD). The data obtained indicated that the S100A1 segment comprising nearly 17 residues have some common residues that interact with both MDM2 and p53-TAD. Further, we synthesized the 17-residue peptide derived from the S100A1 protein and attached it to the cell-penetrating HIV-TAT peptide. The HSQC-NMR competitive binding experiment revealed that Peptide 1 could successfully interfere with the p53-MDM2 interaction. Furthermore, functional effects of the peptide was validated in cancer cells. The results showed that Peptide 1 effectively inhibited cell proliferation, and increased the protein levels of p53 and its downstream p21 in MCF-7 cells. Treatment of Peptide 1 resulted in cell cycle arrest at G2/M phase, and also induced apoptotic cell death at higher concentration. Taken together, the results suggest that disruption of the interaction of p53 and MDM2 by Peptide 1 could activate normal p53 functions, leading to cell cycle arrest and apoptotic cell death in cancer cells. We proposed here that S100A1 could influence the p53-MDM2 interaction credibly and possibly reactivates the wild type p53 pathway.
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Affiliation(s)
- Deepu Dowarha
- Department of Chemistry, National Tsing Hua University, Hsinchu, Taiwan
| | - Ruey-Hwang Chou
- Graduate Institute of Biomedical Sciences and Center for Molecular Medicine, China Medical University, Taichung, Taiwan
- Department of Biotechnology, Asia University, Wufeng, Taichung, Taiwan
- * E-mail: (CY); (RHC)
| | - Chin Yu
- Department of Chemistry, National Tsing Hua University, Hsinchu, Taiwan
- * E-mail: (CY); (RHC)
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13
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Wang X, Wang F, Zhong M, Yarden Y, Fu L. The biomarkers of hyperprogressive disease in PD-1/PD-L1 blockage therapy. Mol Cancer 2020. [PMID: 32359357 DOI: 10.1186/s12943-020-01200-x.] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/10/2022] Open
Abstract
Immune checkpoint inhibitors (ICIs), such as PD-1/PD-L1 antibodies (Abs) and anti-cytotoxic T lymphocyte antigen 4 (CTLA-4) Abs, are effective for patients with various cancers. However, low response rates to ICI monotherapies and even hyperprogressive disease (HPD) have limited the clinical application of ICIs. HPD is a novel pattern of progression, with an unexpected and fast progression in tumor volume and rate, poor survival of patients and early fatality. Considering the limitations of ICI due to HPD incidence, valid biomarkers are urgently needed to predict the occurrence of HPD and the efficacy of ICI. Here, we reviewed and summarized the known biomarkers of HPD, including tumor cell biomarkers, tumor microenvironment biomarkers, laboratory biomarkers and clinical indicators, which provide a potential effective approach for selecting patients sensitive to ICI cancer treatments.
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Affiliation(s)
- Xueping Wang
- State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangdong Esophageal Cancer Institute, Sun Yat-sen University Cancer Center, Guangzhou, China
| | - Fang Wang
- State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangdong Esophageal Cancer Institute, Sun Yat-sen University Cancer Center, Guangzhou, China
| | - Mengjun Zhong
- State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangdong Esophageal Cancer Institute, Sun Yat-sen University Cancer Center, Guangzhou, China
| | - Yosef Yarden
- Department of Biological Regulation, Weizmann Institute of Science, 76100, Rehovot, Israel
| | - Liwu Fu
- State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangdong Esophageal Cancer Institute, Sun Yat-sen University Cancer Center, Guangzhou, China.
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14
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The biomarkers of hyperprogressive disease in PD-1/PD-L1 blockage therapy. Mol Cancer 2020; 19:81. [PMID: 32359357 PMCID: PMC7195736 DOI: 10.1186/s12943-020-01200-x] [Citation(s) in RCA: 91] [Impact Index Per Article: 18.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/04/2020] [Accepted: 04/15/2020] [Indexed: 12/30/2022] Open
Abstract
Immune checkpoint inhibitors (ICIs), such as PD-1/PD-L1 antibodies (Abs) and anti-cytotoxic T lymphocyte antigen 4 (CTLA-4) Abs, are effective for patients with various cancers. However, low response rates to ICI monotherapies and even hyperprogressive disease (HPD) have limited the clinical application of ICIs. HPD is a novel pattern of progression, with an unexpected and fast progression in tumor volume and rate, poor survival of patients and early fatality. Considering the limitations of ICI due to HPD incidence, valid biomarkers are urgently needed to predict the occurrence of HPD and the efficacy of ICI. Here, we reviewed and summarized the known biomarkers of HPD, including tumor cell biomarkers, tumor microenvironment biomarkers, laboratory biomarkers and clinical indicators, which provide a potential effective approach for selecting patients sensitive to ICI cancer treatments.
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15
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Niu C, Wang L, Ye W, Guo S, Bao X, Wang Y, Xia Z, Chen R, Liu C, Lin X, Huang X. CCAT2 contributes to hepatocellular carcinoma progression via inhibiting miR-145 maturation to induce MDM2 expression. J Cell Physiol 2020; 235:6307-6320. [PMID: 32037568 DOI: 10.1002/jcp.29630] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/23/2019] [Accepted: 01/30/2020] [Indexed: 12/19/2022]
Abstract
Long noncoding RNA colon cancer-associated transcript 2 (CCAT2) has been recently found to function as an oncogene in hepatocellular carcinoma (HCC). However, the mechanisms of CCAT2 in HCC development remain to be further explored. In the present study, we found that CCAT2 was abnormally upregulated in HCC cells and tissue specimens, exhibiting an inverse correlation with microRNA (miR)-145 expression. Mechanistic investigation showed that CCAT2 selectively blocked miR-145 processing, leading to decreased mature miR-145 presence. Both the in vitro and in vivo effects of CCAT2 knockdown on the proliferation and metastasis of HCC cells were reversed by miR-145 inhibitor, indicating that miR-145 modulation accounts for CCAT2-meditated HCC progression. Furthermore, miR-145 mimic dramatically suppressed HCC cells' proliferation and metastasis, revealing a tumor suppressor role of miR-145 in HCC. Mechanistically, MDM2 was predicted to be a potential target of miR-145. The luciferase and western blot assay demonstrated that miR-145 mimic largely inhibited MDM2 3'-untranslated region luciferase activity and MDM2 expression, followed by the upregulation of p53/p21 expression. Finally, the coexpression of MDM2 in miR-145 mimic-transfected HCC cells was able to largely compromise the inhibitory effects of miR-145 mimic on HCC cells' proliferation and metastasis in vitro and tumor formation in a xenograft model, confirming MDM2 is the critical mediator of miR-145 in HCC. In summary, our findings indicated that CCAT2 selectively blocks the miR-145 maturation process and plays an oncogene in HCC. Furthermore, a novel CCAT2/miR-145/MDM2 axis was revealed in HCC development and might provide a new target in the molecular treatment of HCC.
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Affiliation(s)
- Chao Niu
- Pediatric Research Institute, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, China
| | - Linlin Wang
- Pediatric Research Institute, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, China
| | - Weijian Ye
- Department of Pharmacy, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, China
| | - Shikun Guo
- Department of Pediatric Surgery, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, China
| | - Xiaozhou Bao
- Department of Pediatric Surgery, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, China
| | - Yongbiao Wang
- Department of Pediatric Surgery, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, China
| | - Zhaobo Xia
- Department of Pediatric Surgery, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, China
| | - Randong Chen
- Department of Pediatric Surgery, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, China
| | - Chong Liu
- Department of Cardiology, The Central Hospital of Lishui City, Lishui, China
| | - Xiaokun Lin
- Department of Pediatric Surgery, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, China
| | - Xiaozhong Huang
- Pediatric Research Institute, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, China.,Department of Pediatric Surgery, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, China
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16
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Kanagasabai T, Venkatesan T, Natarajan U, Alobid S, Alhazzani K, Algahtani M, Rathinavelu A. Regulation of cell cycle by MDM2 in prostate cancer cells through Aurora Kinase-B and p21WAF1 /CIP1 mediated pathways. Cell Signal 2019; 66:109435. [PMID: 31706019 DOI: 10.1016/j.cellsig.2019.109435] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/16/2019] [Revised: 09/23/2019] [Accepted: 10/02/2019] [Indexed: 01/10/2023]
Abstract
Overexpression of MDM2 oncoprotein has been detected in a large number of diverse human malignancies and has been shown to play both p53-dependent and p53-independent roles in oncogenesis. Our study was designed to explore the impact of MDM2 overexpression on the levels of various cell cycle regulatory proteins including Aurora kinase-B (AURK-B), CDC25C and CDK1, which are known to promote tumor progression and increase metastatic potential. Our data from human cell cycle RT2 profiler PCR array experiments revealed significant changes in the expression profile of genes that are involved in different phases of cell cycle regulation in LNCaP-MST (MDM2 transfected) prostate cancer cells. Our current study has demonstrated a significant increase in the expression level of AURK-B, CDC25C, Cyclin A2, Cyclin B and CDK1 in LNCaP-MST cells as compared with wild type LNCaP cells that were modulated by MDM2 specific inhibitor Nutlin-3. In fact, the expression levels of the above- mentioned proteins were significantly altered at both mRNA and protein levels after treating the cells with 20 μM Nutlin-3 for 24h. Additionally, the pro-apoptotic proteins including p53, p21, and Bax were elevated with the concomitant decrease in the key anti-apoptotic proteins following MDM2 inhibitor treatment. Also, Nutlin-3 treated cells demonstrated caspase-3 activation was observed with an in-vitro caspase-3 fluorescent assay performed with caspase 3/7 specific DEVD-amc substrate. Our results offer significant evidence towards the effectiveness of MDM2 inhibition in causing cell cycle arrest via blocking the transmission of signals through AURKB-CDK1 axis and inducing apoptosis in LNCaP-MST cancer cells. It is evident from our data that MDM2 overexpression probably is the primary cause for CDK1 up-regulation in the LNCaP-MST cells, which might have occurred possibly through activation of AURK-B. However, further studies in this direction should shed more light on the intracellular mechanisms involved in the regulation of Aurora kinase-B and CDK1 axis in MDM2 positive cancers.
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Affiliation(s)
- Thanigaivelan Kanagasabai
- Rumbaugh-Goodwin Institute for Cancer Research, Nova Southeastern University, Ft. Lauderdale, FL 33314, USA
| | - Thiagarajan Venkatesan
- Rumbaugh-Goodwin Institute for Cancer Research, Nova Southeastern University, Ft. Lauderdale, FL 33314, USA
| | - Umamaheswari Natarajan
- Rumbaugh-Goodwin Institute for Cancer Research, Nova Southeastern University, Ft. Lauderdale, FL 33314, USA; VRR Institute of Biomedical Sciences, Kattupakkam, Chennai, TN 600056, India
| | - Saad Alobid
- Rumbaugh-Goodwin Institute for Cancer Research, Nova Southeastern University, Ft. Lauderdale, FL 33314, USA; College of Pharmacy, Health Professions Division, Nova Southeastern University, Ft. Lauderdale, FL 33314, USA; College of Pharmacy, King Saud University, Riyadh 12371, Saudi Arabia
| | - Khalid Alhazzani
- Rumbaugh-Goodwin Institute for Cancer Research, Nova Southeastern University, Ft. Lauderdale, FL 33314, USA; College of Pharmacy, Health Professions Division, Nova Southeastern University, Ft. Lauderdale, FL 33314, USA; College of Pharmacy, King Saud University, Riyadh 12371, Saudi Arabia
| | - Mohammad Algahtani
- Rumbaugh-Goodwin Institute for Cancer Research, Nova Southeastern University, Ft. Lauderdale, FL 33314, USA; College of Pharmacy, Health Professions Division, Nova Southeastern University, Ft. Lauderdale, FL 33314, USA; College of Pharmacy, King Saud University, Riyadh 12371, Saudi Arabia
| | - Appu Rathinavelu
- Rumbaugh-Goodwin Institute for Cancer Research, Nova Southeastern University, Ft. Lauderdale, FL 33314, USA; College of Pharmacy, Health Professions Division, Nova Southeastern University, Ft. Lauderdale, FL 33314, USA.
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17
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Wang W, Qin JJ, Rajaei M, Li X, Yu X, Hunt C, Zhang R. Targeting MDM2 for novel molecular therapy: Beyond oncology. Med Res Rev 2019; 40:856-880. [PMID: 31587329 DOI: 10.1002/med.21637] [Citation(s) in RCA: 66] [Impact Index Per Article: 11.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/04/2019] [Revised: 08/20/2019] [Accepted: 08/21/2019] [Indexed: 12/14/2022]
Abstract
The murine double minute 2 (MDM2) oncogene exerts major oncogenic activities in human cancers; it is not only the best-documented negative regulator of the p53 tumor suppressor, but also exerts p53-independent activities. There is an increasing interest in developing MDM2-based targeted therapies. Several classes of MDM2 inhibitors have been evaluated in preclinical models, with a few entering clinical trials, mainly for cancer therapy. However, noncarcinogenic roles for MDM2 have also been identified, demonstrating that MDM2 is involved in many chronic diseases and conditions such as inflammation and autoimmune diseases, dementia and neurodegenerative diseases, heart failure and cardiovascular diseases, nephropathy, diabetes, obesity, and sterility. MDM2 inhibitors have been shown to have promising therapeutic efficacy for treating inflammation and other nonmalignant diseases in preclinical evaluations. Therefore, targeting MDM2 may represent a promising approach for treating and preventing these nonmalignant diseases. In addition, a better understanding of how MDM2 works in nonmalignant diseases may provide new biomarkers for their diagnosis, prognostic prediction, and monitoring of therapeutic outcome. In this review article, we pay special attention to the recent findings related to the roles of MDM2 in the pathogenesis of several nonmalignant diseases, the therapeutic potential of its downregulation or inhibition, and its use as a biomarker.
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Affiliation(s)
- Wei Wang
- Department of Pharmacological and Pharmaceutical Sciences, College of Pharmacy, University of Houston, Houston, Texas.,Drug Discovery Institute, University of Houston, Houston, Texas
| | - Jiang-Jiang Qin
- Department of Pharmacological and Pharmaceutical Sciences, College of Pharmacy, University of Houston, Houston, Texas
| | - Mehrdad Rajaei
- Department of Pharmacological and Pharmaceutical Sciences, College of Pharmacy, University of Houston, Houston, Texas
| | - Xin Li
- Department of Pharmacological and Pharmaceutical Sciences, College of Pharmacy, University of Houston, Houston, Texas
| | - Xiaoyi Yu
- Department of Pharmacological and Pharmaceutical Sciences, College of Pharmacy, University of Houston, Houston, Texas
| | - Courtney Hunt
- Drug Discovery Institute, University of Houston, Houston, Texas
| | - Ruiwen Zhang
- Department of Pharmacological and Pharmaceutical Sciences, College of Pharmacy, University of Houston, Houston, Texas.,Drug Discovery Institute, University of Houston, Houston, Texas
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18
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Bhyan SB, Wee Y, Liu Y, Cummins S, Zhao M. Integrative analysis of common genes and driver mutations implicated in hormone stimulation for four cancers in women. PeerJ 2019; 7:e6872. [PMID: 31205821 PMCID: PMC6556371 DOI: 10.7717/peerj.6872] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/29/2019] [Accepted: 03/28/2019] [Indexed: 12/11/2022] Open
Abstract
Cancer is one of the leading cause of death of women worldwide, and breast, ovarian, endometrial and cervical cancers contribute significantly to this every year. Developing early genetic-based diagnostic tools may be an effective approach to increase the chances of survival and provide more treatment opportunities. However, the current cancer genetic studies are mainly conducted independently and, hence lack of common driver genes involved in cancers in women. To explore the potential common molecular mechanism, we integrated four comprehensive literature-based databases to explore the shared implicated genetic effects. Using a total of 460 endometrial, 2,068 ovarian, 2,308 breast and 537 cervical cancer-implicated genes, we identified 52 genes which are common in all four types of cancers in women. Furthermore, we defined their potential functional role in endogenous hormonal regulation pathways within the context of four cancers in women. For example, these genes are strongly associated with hormonal stimulation, which may facilitate rapid diagnosis and treatment management decision making. Additional mutational analyses on combined the cancer genome atlas datasets consisting of 5,919 gynaecological and breast tumor samples were conducted to identify the frequently mutated genes across cancer types. For those common implicated genes for hormonal stimulants, we found that three quarter of 5,919 samples had genomic alteration with the highest frequency in MYC (22%), followed by NDRG1 (19%), ERBB2 (14%), PTEN (13%), PTGS2 (13%) and CDH1 (11%). We also identified 38 hormone related genes, eight of which are associated with the ovulation cycle. Further systems biology approach of the shared genes identified 20 novel genes, of which 12 were involved in the hormone regulation in these four cancers in women. Identification of common driver genes for hormone stimulation provided an unique angle of involving the potential of the hormone stimulants-related genes for cancer diagnosis and prognosis.
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Affiliation(s)
- Salma Begum Bhyan
- Faculty of Science, Health, Education and Engineering, University of the Sunshine Coast, Sunshine Coast, QLD, Australia
| | - YongKiat Wee
- Faculty of Science, Health, Education and Engineering, University of the Sunshine Coast, Sunshine Coast, QLD, Australia
| | - Yining Liu
- The School of Public Health, Institute for Chemical Carcinogenesis, Guangzhou Medical University, Guangzhou, China
| | - Scott Cummins
- Faculty of Science, Health, Education and Engineering, University of the Sunshine Coast, Sunshine Coast, QLD, Australia
| | - Min Zhao
- Faculty of Science, Health, Education and Engineering, University of the Sunshine Coast, Sunshine Coast, QLD, Australia
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19
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Wang W, Qin JJ, Voruganti S, Nijampatnam B, Velu SE, Ruan KH, Hu M, Zhou J, Zhang R. Discovery and Characterization of Dual Inhibitors of MDM2 and NFAT1 for Pancreatic Cancer Therapy. Cancer Res 2018; 78:5656-5667. [PMID: 30217928 DOI: 10.1158/0008-5472.can-17-3939] [Citation(s) in RCA: 32] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/19/2017] [Revised: 04/12/2018] [Accepted: 08/15/2018] [Indexed: 12/18/2022]
Abstract
Overexpression and activation of the murine double minute 2 (MDM2) or nuclear factor of activated T cells 1 (NFAT1) oncoproteins frequently occur in pancreatic cancer. Most MDM2 inhibitors under development target MDM2-p53 binding and have little or no effect on cancers without functional p53, including pancreatic cancer. Some available compounds indirectly inhibit NFAT1 activity by interfering with calcineurin activity, but there are currently no specific inhibitors against NFAT1. Here we performed a high-throughput virtual and cell-based screening to yield a lead compound (MA242) that can directly bind both MDM2 and NFAT1 with high affinity, induce their protein degradation, and inhibit NFAT1-mediated transcription of MDM2 As a result of this binding, MA242 decreased cell proliferation and induced apoptosis in pancreatic cancer cell lines regardless of p53 status. MA242 alone or in combination with gemcitabine inhibited pancreatic tumor growth and metastasis without any host toxicity. Our data indicate that targeting both MDM2 and NFAT1 represents a novel and effective strategy to treat pancreatic cancer.Significance: These findings suggest that pharmacological inhibition of both MDM2 and NFAT1 is a promising strategy for the treatment of pancreatic cancer, even in tumors lacking functional p53. Cancer Res; 78(19); 5656-67. ©2018 AACR.
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Affiliation(s)
- Wei Wang
- Department of Pharmacological and Pharmaceutical Sciences, College of Pharmacy, University of Houston, Houston, Texas. .,Drug Discovery Institute, University of Houston, Houston, Texas
| | - Jiang-Jiang Qin
- Department of Pharmacological and Pharmaceutical Sciences, College of Pharmacy, University of Houston, Houston, Texas
| | - Sukesh Voruganti
- Department of Pharmaceutical Sciences, School of Pharmacy, Texas Tech University Health Sciences Center, Amarillo, Texas
| | | | - Sadanandan E Velu
- Department of Chemistry, University of Alabama at Birmingham, Birmingham, Alabama
| | - Ke-He Ruan
- Department of Pharmacological and Pharmaceutical Sciences, College of Pharmacy, University of Houston, Houston, Texas
| | - Ming Hu
- Department of Pharmacological and Pharmaceutical Sciences, College of Pharmacy, University of Houston, Houston, Texas.,Drug Discovery Institute, University of Houston, Houston, Texas
| | - Jianwei Zhou
- Department of Molecular Cell Biology and Toxicology, Cancer Center, School of Public Health, Nanjing Medical University, Nanjing, P.R. China
| | - Ruiwen Zhang
- Department of Pharmacological and Pharmaceutical Sciences, College of Pharmacy, University of Houston, Houston, Texas. .,Drug Discovery Institute, University of Houston, Houston, Texas
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20
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Al-Khalaf HH, Aboussekhra A. p16 Controls p53 Protein Expression Through miR-dependent Destabilization of MDM2. Mol Cancer Res 2018; 16:1299-1308. [DOI: 10.1158/1541-7786.mcr-18-0017] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/08/2018] [Revised: 03/22/2018] [Accepted: 04/24/2018] [Indexed: 11/16/2022]
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21
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Zhanfeng N, Chengquan W, Hechun X, Jun W, Lijian Z, Dede M, Wenbin L, Lei Y. Period2 downregulation inhibits glioma cell apoptosis by activating the MDM2-TP53 pathway. Oncotarget 2017; 7:27350-62. [PMID: 27036047 PMCID: PMC5053655 DOI: 10.18632/oncotarget.8439] [Citation(s) in RCA: 26] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/04/2015] [Accepted: 03/16/2016] [Indexed: 12/21/2022] Open
Abstract
The Period2 (Per2) gene is an essential component of the mammalian circadian clock and is strongly linked to glioma occurrence and its response to radiotherapy. Here, we examined the role of Per2 in the response to X-ray-induced DNA damage in U343 glioma cells and in a mouse cancer model. Following low dose X-ray irradiation, we observed that lowering Per2 expression using RNAi reduces DNA damage and cell death in U343 cells and glioma tissue. Additionally, Per2 was associated with increased TP53 activity and was involved in the DNA damage during TP53-mediated apoptosis. These findings suggest that Per2, a core circadian gene, is not only a tumor suppressor gene but can also be regarded as an upstream regulator of TP53. It thus appears that Per2 is an important inhibitor of tumor growth that acts by increasing TP53 expression, DNA damage repair, and apoptosis.
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Affiliation(s)
- Niu Zhanfeng
- Department of Neurosurgery, The General Hospital of Ningxia Medical University, Yinchuan, 750004, China.,Incubation Base of National Key Laboratory for Cerebrocranial Diseases, Ningxia Medical University, Yinchuan, 750004, China
| | - Wang Chengquan
- The People's Hospital of Liaocheng City, Liaocheng, 252000, China
| | - Xia Hechun
- Department of Neurosurgery, The General Hospital of Ningxia Medical University, Yinchuan, 750004, China.,Incubation Base of National Key Laboratory for Cerebrocranial Diseases, Ningxia Medical University, Yinchuan, 750004, China
| | - Wang Jun
- Ningxia Medical University, Yinchuan, 750004, China.,Incubation Base of National Key Laboratory for Cerebrocranial Diseases, Ningxia Medical University, Yinchuan, 750004, China
| | - Zhang Lijian
- Ningxia Medical University, Yinchuan, 750004, China.,Incubation Base of National Key Laboratory for Cerebrocranial Diseases, Ningxia Medical University, Yinchuan, 750004, China
| | - Ma Dede
- Ningxia Medical University, Yinchuan, 750004, China.,Incubation Base of National Key Laboratory for Cerebrocranial Diseases, Ningxia Medical University, Yinchuan, 750004, China
| | - Liu Wenbin
- Ningxia Medical University, Yinchuan, 750004, China.,Incubation Base of National Key Laboratory for Cerebrocranial Diseases, Ningxia Medical University, Yinchuan, 750004, China
| | - Yin Lei
- Department of ICU, The General Hospital of Ningxia Medical University, Yinchuan, 750004, China.,Incubation Base of National Key Laboratory for Cerebrocranial Diseases, Ningxia Medical University, Yinchuan, 750004, China
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Amanullah A, Upadhyay A, Joshi V, Mishra R, Jana NR, Mishra A. Progressing neurobiological strategies against proteostasis failure: Challenges in neurodegeneration. Prog Neurobiol 2017; 159:1-38. [DOI: 10.1016/j.pneurobio.2017.08.005] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/28/2017] [Revised: 06/01/2017] [Accepted: 08/25/2017] [Indexed: 02/07/2023]
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Nutlin-3, an Antagonist of MDM2, Enhances the Radiosensitivity of Esophageal Squamous Cancer with Wild-Type p53. Pathol Oncol Res 2017; 24:75-81. [DOI: 10.1007/s12253-017-0215-5] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/26/2016] [Accepted: 03/10/2017] [Indexed: 12/13/2022]
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Wagner AJ, Banerji U, Mahipal A, Somaiah N, Hirsch H, Fancourt C, Johnson-Levonas AO, Lam R, Meister AK, Russo G, Knox CD, Rose S, Hong DS. Phase I Trial of the Human Double Minute 2 Inhibitor MK-8242 in Patients With Advanced Solid Tumors. J Clin Oncol 2017; 35:1304-1311. [PMID: 28240971 DOI: 10.1200/jco.2016.70.7117] [Citation(s) in RCA: 79] [Impact Index Per Article: 9.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/20/2022] Open
Abstract
Purpose To evaluate MK-8242 in patients with wild-type TP53 advanced solid tumors. Patients and Methods MK-8242 was administered orally twice a day on days 1 to 7 in 21-day cycles. The recommended phase II dose (RP2D) was determined on the basis of safety, tolerability, pharmacokinetics (PK), and by mRNA expression of the p53 target gene pleckstrin homology-like domain, family A, member 3 ( PHLDA3). Other objectives were to characterize the PK/pharmacodynamic (PD) relationship, correlate biomarkers with response, and assess tumor response. Results Forty-seven patients received MK-8242 across eight doses that ranged from 60 to 500 mg. Initially, six patients developed dose-limiting toxicities (DLTs): grade (G) 2 nausea at 120 mg; G3 fatigue at 250 mg; G2 nausea and G4 thrombocytopenia at 350 mg; and G3 vomiting and G3 diarrhea at 500 mg. DLT criteria were revised to permit management of GI toxicities. Dosing was resumed at 400 mg, and four additional DLTs were observed: G4 neutropenia and G4 thrombocytopenia at 400 mg and G4 thrombocytopenia (two patients) at 500 mg. Other drug-related G3 and G4 events included anemia, leukopenia, pancytopenia, nausea, hyperbilirubinemia, hypophosphatemia, and anorexia. On the basis of safety, tolerability, PK, and PD, the RP2D was established at 400 mg (15 evaluable patients experienced two DLTs). PK for 400 mg (day 7) showed Cmax 3.07 μM, Tmax 3.0 hours, t1/2 (half-life) 6.6 hours, CL/F (apparent clearance) 28.9 L/h, and Vd/F (apparent volume) 274 L. Blood PHLDA3 mRNA expression correlated with drug exposure ( R2 = 0.68; P < .001). In 41 patients with postbaseline scans, three patients with liposarcoma achieved a partial response (at 250, 400, and 500 mg), 31 showed stable disease, and eight had progressive disease. In total, 27 patients with liposarcoma had a median progression-free survival of 237 days. Conclusion At the RP2D of 400 mg twice a day, MK-8242 activated the p53 pathway with an acceptable safety and tolerability profile. The observed clinical activity (partial response and prolonged progression-free survival) provides an impetus for further study of HDM2 inhibitors in liposarcoma.
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Affiliation(s)
- Andrew J Wagner
- Andrew J. Wagner, Dana-Farber Cancer Institute, Boston, MA; Udai Banerji, The Institute of Cancer Research and The Royal Marsden NHS Foundation Trust, London, United Kingdom; Amit Mahipal, Moffitt Cancer Center, Tampa, FL; Neeta Somaiah and David S. Hong, The University of Texas MD Anderson Cancer Center, Houston, TX; and Heather Hirsch, Craig Fancourt, Amy O. Johnson-Levonas, Raymond Lam, Amy K. Meister, Giuseppe Russo, Clayton D. Knox, and Shelonitda Rose, Merck & Co., Kenilworth, NJ
| | - Udai Banerji
- Andrew J. Wagner, Dana-Farber Cancer Institute, Boston, MA; Udai Banerji, The Institute of Cancer Research and The Royal Marsden NHS Foundation Trust, London, United Kingdom; Amit Mahipal, Moffitt Cancer Center, Tampa, FL; Neeta Somaiah and David S. Hong, The University of Texas MD Anderson Cancer Center, Houston, TX; and Heather Hirsch, Craig Fancourt, Amy O. Johnson-Levonas, Raymond Lam, Amy K. Meister, Giuseppe Russo, Clayton D. Knox, and Shelonitda Rose, Merck & Co., Kenilworth, NJ
| | - Amit Mahipal
- Andrew J. Wagner, Dana-Farber Cancer Institute, Boston, MA; Udai Banerji, The Institute of Cancer Research and The Royal Marsden NHS Foundation Trust, London, United Kingdom; Amit Mahipal, Moffitt Cancer Center, Tampa, FL; Neeta Somaiah and David S. Hong, The University of Texas MD Anderson Cancer Center, Houston, TX; and Heather Hirsch, Craig Fancourt, Amy O. Johnson-Levonas, Raymond Lam, Amy K. Meister, Giuseppe Russo, Clayton D. Knox, and Shelonitda Rose, Merck & Co., Kenilworth, NJ
| | - Neeta Somaiah
- Andrew J. Wagner, Dana-Farber Cancer Institute, Boston, MA; Udai Banerji, The Institute of Cancer Research and The Royal Marsden NHS Foundation Trust, London, United Kingdom; Amit Mahipal, Moffitt Cancer Center, Tampa, FL; Neeta Somaiah and David S. Hong, The University of Texas MD Anderson Cancer Center, Houston, TX; and Heather Hirsch, Craig Fancourt, Amy O. Johnson-Levonas, Raymond Lam, Amy K. Meister, Giuseppe Russo, Clayton D. Knox, and Shelonitda Rose, Merck & Co., Kenilworth, NJ
| | - Heather Hirsch
- Andrew J. Wagner, Dana-Farber Cancer Institute, Boston, MA; Udai Banerji, The Institute of Cancer Research and The Royal Marsden NHS Foundation Trust, London, United Kingdom; Amit Mahipal, Moffitt Cancer Center, Tampa, FL; Neeta Somaiah and David S. Hong, The University of Texas MD Anderson Cancer Center, Houston, TX; and Heather Hirsch, Craig Fancourt, Amy O. Johnson-Levonas, Raymond Lam, Amy K. Meister, Giuseppe Russo, Clayton D. Knox, and Shelonitda Rose, Merck & Co., Kenilworth, NJ
| | - Craig Fancourt
- Andrew J. Wagner, Dana-Farber Cancer Institute, Boston, MA; Udai Banerji, The Institute of Cancer Research and The Royal Marsden NHS Foundation Trust, London, United Kingdom; Amit Mahipal, Moffitt Cancer Center, Tampa, FL; Neeta Somaiah and David S. Hong, The University of Texas MD Anderson Cancer Center, Houston, TX; and Heather Hirsch, Craig Fancourt, Amy O. Johnson-Levonas, Raymond Lam, Amy K. Meister, Giuseppe Russo, Clayton D. Knox, and Shelonitda Rose, Merck & Co., Kenilworth, NJ
| | - Amy O Johnson-Levonas
- Andrew J. Wagner, Dana-Farber Cancer Institute, Boston, MA; Udai Banerji, The Institute of Cancer Research and The Royal Marsden NHS Foundation Trust, London, United Kingdom; Amit Mahipal, Moffitt Cancer Center, Tampa, FL; Neeta Somaiah and David S. Hong, The University of Texas MD Anderson Cancer Center, Houston, TX; and Heather Hirsch, Craig Fancourt, Amy O. Johnson-Levonas, Raymond Lam, Amy K. Meister, Giuseppe Russo, Clayton D. Knox, and Shelonitda Rose, Merck & Co., Kenilworth, NJ
| | - Raymond Lam
- Andrew J. Wagner, Dana-Farber Cancer Institute, Boston, MA; Udai Banerji, The Institute of Cancer Research and The Royal Marsden NHS Foundation Trust, London, United Kingdom; Amit Mahipal, Moffitt Cancer Center, Tampa, FL; Neeta Somaiah and David S. Hong, The University of Texas MD Anderson Cancer Center, Houston, TX; and Heather Hirsch, Craig Fancourt, Amy O. Johnson-Levonas, Raymond Lam, Amy K. Meister, Giuseppe Russo, Clayton D. Knox, and Shelonitda Rose, Merck & Co., Kenilworth, NJ
| | - Amy K Meister
- Andrew J. Wagner, Dana-Farber Cancer Institute, Boston, MA; Udai Banerji, The Institute of Cancer Research and The Royal Marsden NHS Foundation Trust, London, United Kingdom; Amit Mahipal, Moffitt Cancer Center, Tampa, FL; Neeta Somaiah and David S. Hong, The University of Texas MD Anderson Cancer Center, Houston, TX; and Heather Hirsch, Craig Fancourt, Amy O. Johnson-Levonas, Raymond Lam, Amy K. Meister, Giuseppe Russo, Clayton D. Knox, and Shelonitda Rose, Merck & Co., Kenilworth, NJ
| | - Giuseppe Russo
- Andrew J. Wagner, Dana-Farber Cancer Institute, Boston, MA; Udai Banerji, The Institute of Cancer Research and The Royal Marsden NHS Foundation Trust, London, United Kingdom; Amit Mahipal, Moffitt Cancer Center, Tampa, FL; Neeta Somaiah and David S. Hong, The University of Texas MD Anderson Cancer Center, Houston, TX; and Heather Hirsch, Craig Fancourt, Amy O. Johnson-Levonas, Raymond Lam, Amy K. Meister, Giuseppe Russo, Clayton D. Knox, and Shelonitda Rose, Merck & Co., Kenilworth, NJ
| | - Clayton D Knox
- Andrew J. Wagner, Dana-Farber Cancer Institute, Boston, MA; Udai Banerji, The Institute of Cancer Research and The Royal Marsden NHS Foundation Trust, London, United Kingdom; Amit Mahipal, Moffitt Cancer Center, Tampa, FL; Neeta Somaiah and David S. Hong, The University of Texas MD Anderson Cancer Center, Houston, TX; and Heather Hirsch, Craig Fancourt, Amy O. Johnson-Levonas, Raymond Lam, Amy K. Meister, Giuseppe Russo, Clayton D. Knox, and Shelonitda Rose, Merck & Co., Kenilworth, NJ
| | - Shelonitda Rose
- Andrew J. Wagner, Dana-Farber Cancer Institute, Boston, MA; Udai Banerji, The Institute of Cancer Research and The Royal Marsden NHS Foundation Trust, London, United Kingdom; Amit Mahipal, Moffitt Cancer Center, Tampa, FL; Neeta Somaiah and David S. Hong, The University of Texas MD Anderson Cancer Center, Houston, TX; and Heather Hirsch, Craig Fancourt, Amy O. Johnson-Levonas, Raymond Lam, Amy K. Meister, Giuseppe Russo, Clayton D. Knox, and Shelonitda Rose, Merck & Co., Kenilworth, NJ
| | - David S Hong
- Andrew J. Wagner, Dana-Farber Cancer Institute, Boston, MA; Udai Banerji, The Institute of Cancer Research and The Royal Marsden NHS Foundation Trust, London, United Kingdom; Amit Mahipal, Moffitt Cancer Center, Tampa, FL; Neeta Somaiah and David S. Hong, The University of Texas MD Anderson Cancer Center, Houston, TX; and Heather Hirsch, Craig Fancourt, Amy O. Johnson-Levonas, Raymond Lam, Amy K. Meister, Giuseppe Russo, Clayton D. Knox, and Shelonitda Rose, Merck & Co., Kenilworth, NJ
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Hernández-Monge J, Rousset-Roman AB, Medina-Medina I, Olivares-Illana V. Dual function of MDM2 and MDMX toward the tumor suppressors p53 and RB. Genes Cancer 2016; 7:278-287. [PMID: 28050229 PMCID: PMC5115168 DOI: 10.18632/genesandcancer.120] [Citation(s) in RCA: 30] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/04/2023] Open
Abstract
The orchestrated crosstalk between the retinoblastoma (RB) and p53 pathways contributes to preserving proper homeostasis within the cell. The deregulation of one or both pathways is a common factor in the development of most types of human cancer. The proto-oncoproteins MDMX and MDM2 are the main regulators of the well- known tumor suppressor p53 protein. Under normal conditions, MDM2 and MDMX inhibit p53, either via repression of its transcriptional activity by protein-protein interaction, or via polyubiquitination as a result of MDM2-E3 ubiquitin ligase activity, for which MDM2 needs to dimerize with MDMX. Under genotoxic stress conditions, both become positive regulators of p53. The ATM-dependent phosphorylation of MDM2 and MDMX allow them to bind p53 mRNA, these interactions promote p53 translation. MDM2 and MDMX are also being revealed as effective regulators of the RB protein. MDM2 is able to degrade RB by two different mechanisms, that is, by ubiquitin dependent and independent pathways. MDMX enhances the ability of MDM2 to bind and degrade RB protein. However, MDMX also seems to stabilize RB through interaction and competition with MDM2. Here, we will contextualize the findings that suggest that the MDM2 and MDMX proteins have a dual function on both p53 and RB.
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Affiliation(s)
- Jesús Hernández-Monge
- Instituto de Física, Universidad Autónoma de San Luis Potosí, Av Manuel Nava No 6 Zona Universitaria CP 78290. SLP, México
| | - Adriana Berenice Rousset-Roman
- Instituto de Física, Universidad Autónoma de San Luis Potosí, Av Manuel Nava No 6 Zona Universitaria CP 78290. SLP, México
| | - Ixaura Medina-Medina
- Instituto de Física, Universidad Autónoma de San Luis Potosí, Av Manuel Nava No 6 Zona Universitaria CP 78290. SLP, México
| | - Vanesa Olivares-Illana
- Instituto de Física, Universidad Autónoma de San Luis Potosí, Av Manuel Nava No 6 Zona Universitaria CP 78290. SLP, México
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Xie C, Wu B, Chen B, Shi Q, Guo J, Fan Z, Huang Y. Histone deacetylase inhibitor sodium butyrate suppresses proliferation and promotes apoptosis in osteosarcoma cells by regulation of the MDM2-p53 signaling. Onco Targets Ther 2016; 9:4005-13. [PMID: 27445491 PMCID: PMC4938147 DOI: 10.2147/ott.s105418] [Citation(s) in RCA: 28] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/29/2022] Open
Abstract
Histone deacetylase inhibitors have been reported to induce tumor cell growth arrest, differentiation, and apoptosis. This study aimed to investigate the effects of one histone deacetylase inhibitor - sodium butyrate (SB) - on osteosarcoma (OS) cell proliferation and apoptosis and also the molecular mechanisms by which SB exerts regulatory effects on OS cells. U2OS and MG63 cells were treated with SB at various concentrations. Then, cell proliferation and apoptosis were determined by 3-(4, 5-dimethylthiazol-2-yl)-2, 5-diphenyltetrazolium bromide and flow cytometry assays, respectively; the expression of Ki67, Bax, Bcl-2, MDM2, and p53 proteins was determined by using Western blot assay. The results showed that SB suppressed proliferation in a concentration-dependent manner and promoted apoptosis of OS cells. In addition, SB enhanced p53 expression and decreased MDM2 expression, indicating that SB can regulate MDM2-p53 feedback loop. p53 inhibited proliferation and promoted apoptosis, whereas MDM2 promoted proliferation and suppressed apoptosis, which indicated that functional effect of SB on OS cell lines at least in part depended on the MDM2-p53 signaling. We also explored the effect of SB on OS cells in vivo and found that SB suppressed the growth of OS cells with no noticeable effect on activity and body weight of mice in vivo. These findings will offer new clues for OS development and progression and offer SB as a potent targeted agent for OS treatment.
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Affiliation(s)
- Chuhai Xie
- Department of Orthopedics, The Second Affiliated Hospital of Guangzhou Medical University, Guangzhou, People's Republic of China
| | - Boyi Wu
- Department of Orthopedics, The Second Affiliated Hospital of Guangzhou Medical University, Guangzhou, People's Republic of China
| | - Binwei Chen
- Department of Orthopedics, The Second Affiliated Hospital of Guangzhou Medical University, Guangzhou, People's Republic of China
| | - Qunwei Shi
- Department of Orthopedics, The Second Affiliated Hospital of Guangzhou Medical University, Guangzhou, People's Republic of China
| | - Jianhong Guo
- Department of Orthopedics, The Second Affiliated Hospital of Guangzhou Medical University, Guangzhou, People's Republic of China
| | - Ziwen Fan
- Department of Orthopedics, The Second Affiliated Hospital of Guangzhou Medical University, Guangzhou, People's Republic of China
| | - Yan Huang
- Department of Orthopedics, The Second Affiliated Hospital of Guangzhou Medical University, Guangzhou, People's Republic of China
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Wang W, Nijampatnam B, Velu SE, Zhang R. Discovery and development of synthetic tricyclic pyrroloquinone (TPQ) alkaloid analogs for human cancer therapy. Front Chem Sci Eng 2016. [DOI: 10.1007/s11705-016-1562-6] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/04/2023]
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Jiang YW, Zhang ZM, Feng JM, Zhang P, Yang B, Zhao Y, Wang WX, Zhang BC, Rao ZG. Clinical significance of expression of murine double minute 2 and ribosomal protein L23 in gastric cancer. Shijie Huaren Xiaohua Zazhi 2016; 24:513-520. [DOI: 10.11569/wcjd.v24.i4.513] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
AIM: To detect the expression of murine double minute 2 (MDM2) and ribosomal protein L23 (RPL23) in gastric cancer and explore their biological significance in the development of gastric cancer.
METHODS: The expression of MDM2 and RPL23 was detected by immunohistochemistry in 90 human gastric carcinoma specimens and 30 normal gastric tissue specimens. The correlation of MDM2 and RPL23 expression with the clinicopathologic features of gastric carcinoma was analyzed statistically.
RESULTS: The positive expression rate of MDM2 in gastric cancer tissues was significantly higher than that in the control group (62.2% vs 40%, P < 0.05), while the positive rate of RPL23 expression was significantly lower in gastric cancer tissues (30% vs 63.3%, P < 0.05). The expression of MDM2 and RPL23 in gastric cancer was negatively correlated (r = -0.23, P = 0.029). Multivariate analysis showed that overexpression of MDM2, low expression of RPL23, lymph node metastasis, depth of invasion and tumor size were significant prognostic factors.
CONCLUSION: MDM2 and RPL23 expression may be associated with the development of gastric cancer, and they may be used as prognostic markers and new therapeutic targets in gastric cancer.
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Zekri ARN, Hassan ZK, Bahnassy AA, Khaled HM, El-Rouby MN, Haggag RM, Abu-Taleb FM. Differentially expressed genes in metastatic advanced Egyptian bladder cancer. Asian Pac J Cancer Prev 2016; 16:3543-9. [PMID: 25921176 DOI: 10.7314/apjcp.2015.16.8.3543] [Citation(s) in RCA: 28] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/10/2022] Open
Abstract
BACKGROUND Bladder cancer is one of the most common cancers worldwide. Gene expression profiling using microarray technologies improves the understanding of cancer biology. The aim of this study was to determine the gene expression profile in Egyptian bladder cancer patients. MATERIALS AND METHODS Samples from 29 human bladder cancers and adjacent non-neoplastic tissues were analyzed by cDNA microarray, with hierarchical clustering and multidimensional analysis. RESULTS Five hundred and sixteen genes were differentially expressed of which SOS1, HDAC2, PLXNC1, GTSE1, ULK2, IRS2, ABCA12, TOP3A, HES1, and SRP68 genes were involved in 33 different pathways. The most frequently detected genes were: SOS1 in 20 different pathways; HDAC2 in 5 different pathways; IRS2 in 3 different pathways. There were 388 down-regulated genes. PLCB2 was involved in 11 different pathways, MDM2 in 9 pathways, FZD4 in 5 pathways, p15 and FGF12 in 4 pathways, POLE2 in 3 pathways, and MCM4 and POLR2E in 2 pathways. Thirty genes showed significant differences between transitional cell cancer (TCC) and squamous cell cancer (SCC) samples. Unsupervised cluster analysis of DNA microarray data revealed a clear distinction between low and high grade tumors. In addition 26 genes showed significant differences between low and high tumor stages, including fragile histidine triad, Ras and sialyltransferase 8 (alpha) and 16 showed significant differences between low and high tumor grades, like methionine adenosyl transferase II, beta. CONCLUSIONS The present study identified some genes, that can be used as molecular biomarkers or target genes in Egyptian bladder cancer patients.
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Affiliation(s)
- Abdel-Rahman N Zekri
- Virology and Immunology Unit, Cancer Biology Department, National Cancer Institute, Cairo University, Cairo, Egypt E-mail :
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Zhou R, Lu Z, Liu K, Guo J, Liu J, Zhou Y, Yang J, Mi M, Xu H. Platycodin D induces tumor growth arrest by activating FOXO3a expression in prostate cancer in vitro and in vivo. Curr Cancer Drug Targets 2015; 14:860-71. [PMID: 25431082 PMCID: PMC4997962 DOI: 10.2174/1568009614666141128104642] [Citation(s) in RCA: 23] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/31/2014] [Revised: 11/14/2014] [Accepted: 11/27/2014] [Indexed: 12/18/2022]
Abstract
Platycodin D (PD), a major saponin derived from Platycodin grandiflorum, exerted cytotoxicity against prostate cancer cell lines (PC3, DU145 and LNCaP cells) with IC50 values in the range of 11.17 to 26.13μmol/L, whereas RWPE-1cells (a non-malignant human prostate epithelial cell line) were not significantly affected. A further study in these cell lines showed that PD could potently affect cell proliferation (indicated by the bromodeoxyuridine assay), induce cell apoptosis (determined by Annexin V-FITC flow cytometry) and cause cell cycle arrest (indicated by PI staining). After being treated with PD for 48 hours, DU145 and LNCaP cells were arrested in the G0 /G1 phase, and PC3 cells were arrested in the G2/M phase. A Western blotting analysis indicated that PD increased the expression of the FOXO3a transcription factor, decreased the expression of p-FOXO3a and MDM2 and increased the expression of FOXO-responsive genes, p21 and p27. MDM2 silencing (transiently by siRNA-MDM2) increased the PD-induced FOXO3a protein expression, while MDM2 overexpression (in cells transiently transfected with a pcDNA3-MDM2 plasmid) decreased the PD-induced expression of the FOXO3a protein. Moreover, PD dose-dependently inhibited the growth of PC3 xenograft tumors in BALB/c nude mice. A Western blotting analysis of the excised xenograft tumors indicated that similar changes in protein expression also occurred in vivo. These results suggest that PD exhibits significant activity against prostate cancer in vitro and in vivo. The FOXO3a transcription factor appears to be involved in the activity of PD. Together, all of these findings provide a basis for the future development of this agent for human prostate cancer therapy.
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Affiliation(s)
| | | | | | | | | | | | | | | | - Hongxia Xu
- Department of Nutrition, Daping Hospital and Research Institute of Surgery, Third Military Medical University, Chongqing 400042, China.
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Tan BX, Khoo KH, Lim TM, Lane DP. High Mdm4 levels suppress p53 activity and enhance its half-life in acute myeloid leukaemia. Oncotarget 2015; 5:933-43. [PMID: 24659749 PMCID: PMC4011595 DOI: 10.18632/oncotarget.1559] [Citation(s) in RCA: 26] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/30/2023] Open
Abstract
Although p53 is found mutated in almost 50% of all cancers, p53 mutations in leukaemia are relatively rare. Acute myeloid leukaemia (AML) cells employ other strategies to inactivate their wild type p53 (WTp53), like the overexpression of the p53 negative regulators Mdm2 and Mdm4. As such, AMLs are excellent candidates for therapeutics involving the reactivation of their WTp53 to restrict and destroy cancer cells, and the Mdm2 antagonist nutlin-3 is one such promising agent. Using AML cell lines with WTp53, we identified stable and high levels of p53 in the OCI/AML-2 cell lines. We demonstrate that this nutlin-3 sensitive cell line overexpressed Mdm4 to sequester, stabilise and inhibit p53 in the cytoplasm. We also show that elevated Mdm4 competed with Mdm2-p53 interaction and therefore extended p53 half-life while preventing p53 transcriptional activity. Our results provide biochemical evidence on the dynamics of the p53-Mdm2-Mdm4 interactions in affecting p53 levels and activity, and unlike previously reported findings derived from genetically manipulated systems, AML cells with naturally high levels of Mdm4 remain sensitive to nutlin treatment.
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Association of p53 and mdm2 in the development and progression of non-small cell lung cancer. Tumour Biol 2015; 36:5425-32. [DOI: 10.1007/s13277-015-3208-6] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/30/2014] [Accepted: 02/03/2015] [Indexed: 10/24/2022] Open
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Nag S, Qin JJ, Voruganti S, Wang MH, Sharma H, Patil S, Buolamwini JK, Wang W, Zhang R. Development and validation of a rapid HPLC method for quantitation of SP-141, a novel pyrido[b]indole anticancer agent, and an initial pharmacokinetic study in mice. Biomed Chromatogr 2014; 29:654-63. [PMID: 25294254 DOI: 10.1002/bmc.3327] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/18/2013] [Revised: 05/31/2014] [Accepted: 08/15/2014] [Indexed: 11/07/2022]
Abstract
There is an increasing interest in targeting the MDM2 oncogene for cancer therapy. SP-141, a novel designed small molecule MDM2 inhibitor, exerts excellent in vitro and in vivo anticancer activity. To facilitate the preclinical development of this candidate anticancer agent, we have developed an HPLC method for the quantitative analysis of SP-141. The method was validated to be precise, accurate, and specific, with a linear range of 16.2-32,400 ng/mL in plasma, 16.2-6480 ng/mL in homogenates of brain, heart, liver, kidneys, lungs, muscle and tumor, and 32.4-6480 ng/mL in spleen homogenates. The lower limit of quantification was 16.2 ng/mL in plasma and all the tissue homogenates, except for spleen homogenates, where it was 32.4 ng/mL. The intra- and inter-assay precisions (coefficient of variation) were between 0.86 and 13.39%, and accuracies (relative errors) ranged from -8.50 to 13.92%. The relative recoveries were 85.6-113.38%. SP-141 was stable in mouse plasma, modestly plasma bound and metabolized by S9 microsomal enzymes. We performed an initial pharmacokinetic study in tumor-bearing nude mice, demonstrating that SP-141 has a short half-life in plasma and wide tissue distribution. In summary, this HPLC method can be used in future preclinical and clinical investigations of SP-141.
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Affiliation(s)
- Subhasree Nag
- Department of Pharmaceutical Sciences, School of Pharmacy, Texas Tech University Health Sciences Center, Amarillo, TX, 79106, USA
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Wang W, Qin JJ, Voruganti S, Wang MH, Sharma H, Patil S, Zhou J, Wang H, Mukhopadhyay D, Buolamwini JK, Zhang R. Identification of a new class of MDM2 inhibitor that inhibits growth of orthotopic pancreatic tumors in mice. Gastroenterology 2014; 147:893-902.e2. [PMID: 25016295 PMCID: PMC4170027 DOI: 10.1053/j.gastro.2014.07.001] [Citation(s) in RCA: 66] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/25/2013] [Revised: 06/02/2014] [Accepted: 07/07/2014] [Indexed: 01/21/2023]
Abstract
BACKGROUND & AIMS The oncogene MDM2, which encodes an E3 ubiquitin ligase, is overexpressed in pancreatic cancers and is therefore a therapeutic target. Current inhibitors of MDM2 target the interaction between MDM2 and P53; these would have no effect on cancer cells that do not express full-length P53, including many pancreatic cancer cells. We searched for a compound that specifically inhibits MDM2 itself. METHODS We performed a virtual screen and structure-based design to identify specific inhibitors of MDM2. We tested the activities of compounds identified on viability, proliferation, and protein levels of HPAC, Panc-1, AsPC-1, and Mia-Paca-2 pancreatic cancer cell lines. We tested whether intraperitoneal injections of one of the compounds identified affected growth of xenograft tumors from Panc-1 cells, or orthotopic tumors from Panc-1 and AsPC-1 cells (injected into pancreata), in nude mice. RESULTS We identified a compound, called SP141, which bound directly to MDM2, promoting its auto-ubiquitination and degradation by the proteasome. The compound reduced levels of MDM2 in pancreatic cancer cell lines, as well as their proliferation, with 50% inhibitory concentrations <0.5 μM (0.38-0.50 μM). Increasing concentrations of SP141 induced increasing levels of apoptosis and G2-M-phase arrest of pancreatic cancer cell lines, whether or not they expressed functional P53. Injection of nude mice with SP141 (40 mg/kg/d) inhibited growth of xenograft tumors (by 75% compared with control mice), and led to regression of orthotopic tumors. CONCLUSIONS In a screen for specific inhibitors of MDM2, we identified a compound called SP141 that reduces levels of MDM2 in pancreatic cancer cell lines, as well as their proliferation and ability to form tumors in nude mice. SP141 is a new class of MDM2 inhibitor that promotes MDM2 auto-ubiquitination and degradation. It might be further developed as a therapeutic agent for pancreatic cancer.
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Affiliation(s)
- Wei Wang
- Department of Pharmaceutical Sciences, School of Pharmacy, Texas Tech University Health Sciences Center, Amarillo, Texas; Cancer Biology Center, School of Pharmacy, Texas Tech University Health Sciences Center, Amarillo, Texas
| | - Jiang-Jiang Qin
- Department of Pharmaceutical Sciences, School of Pharmacy, Texas Tech University Health Sciences Center, Amarillo, Texas
| | - Sukesh Voruganti
- Department of Pharmaceutical Sciences, School of Pharmacy, Texas Tech University Health Sciences Center, Amarillo, Texas
| | - Ming-Hai Wang
- Cancer Biology Center, School of Pharmacy, Texas Tech University Health Sciences Center, Amarillo, Texas; Department of Biomedical Sciences, School of Pharmacy, Texas Tech University Health Sciences Center, Amarillo, Texas
| | - Horrick Sharma
- Department of Pharmaceutical Sciences, College of Pharmacy, University of Tennessee Health Science Center, Memphis, Tennessee
| | - Shivaputra Patil
- Department of Pharmaceutical Sciences, College of Pharmacy, University of Tennessee Health Science Center, Memphis, Tennessee
| | - Jianwei Zhou
- Department of Molecular Cell Biology and Toxicology, Cancer Center, School of Public Health, Nanjing Medical University, Nanjing, China
| | - Hui Wang
- Key Laboratory of Food Safety Research Center, Institute for Nutritional Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai, China
| | - Debabrata Mukhopadhyay
- Department of Biochemistry and Molecular Biology, Mayo Clinic College of Medicine, Rochester, Minnesota
| | - John K Buolamwini
- Department of Pharmaceutical Sciences, College of Pharmacy, University of Tennessee Health Science Center, Memphis, Tennessee.
| | - Ruiwen Zhang
- Department of Pharmaceutical Sciences, School of Pharmacy, Texas Tech University Health Sciences Center, Amarillo, Texas; Cancer Biology Center, School of Pharmacy, Texas Tech University Health Sciences Center, Amarillo, Texas.
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Wang W, Qin JJ, Voruganti S, Srivenugopal KS, Nag S, Patil S, Sharma H, Wang MH, Wang H, Buolamwini JK, Zhang R. The pyrido[b]indole MDM2 inhibitor SP-141 exerts potent therapeutic effects in breast cancer models. Nat Commun 2014; 5:5086. [PMID: 25271708 PMCID: PMC6774205 DOI: 10.1038/ncomms6086] [Citation(s) in RCA: 57] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/24/2014] [Accepted: 08/25/2014] [Indexed: 12/16/2022] Open
Abstract
A requirement for Mouse Double Minute 2 (MDM2) oncogene activation has been suggested to be associated with cancer progression and metastasis, including breast cancer. To date, most MDM2 inhibitors have been designed to block the MDM2-p53-binding interphase, and have low or no efficacy against advanced breast cancer with mutant or deficient p53. Here we use a high-throughput screening and computer-aided, structure-based rational drug design, and identify a lead compound, SP-141, which can directly bind to MDM2, inhibit MDM2 expression and induce its autoubiquitination and proteasomal degradation. SP-141 has strong in vitro and in vivo antibreast cancer activity, with no apparent host toxicity. While further investigation is needed, our data indicate that SP-141 is a novel targeted therapeutic agent that may especially benefit patients with advanced disease.
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Affiliation(s)
- Wei Wang
- 1] Department of Pharmaceutical Sciences, School of Pharmacy, Texas Tech University Health Sciences Center, Amarillo, Texas 79106, USA [2] Cancer Biology Center, School of Pharmacy, Texas Tech University Health Sciences Center, Amarillo, Texas 79106, USA
| | - Jiang-Jiang Qin
- Department of Pharmaceutical Sciences, School of Pharmacy, Texas Tech University Health Sciences Center, Amarillo, Texas 79106, USA
| | - Sukesh Voruganti
- Department of Pharmaceutical Sciences, School of Pharmacy, Texas Tech University Health Sciences Center, Amarillo, Texas 79106, USA
| | - Kalkunte S Srivenugopal
- 1] Cancer Biology Center, School of Pharmacy, Texas Tech University Health Sciences Center, Amarillo, Texas 79106, USA [2] Department of Biomedical Sciences, School of Pharmacy, Texas Tech University Health Sciences Center, Amarillo, Texas 79106, USA
| | - Subhasree Nag
- Department of Pharmaceutical Sciences, School of Pharmacy, Texas Tech University Health Sciences Center, Amarillo, Texas 79106, USA
| | - Shivaputra Patil
- Department of Pharmaceutical Sciences, College of Pharmacy, University of Tennessee Health Science Center, Memphis, Tennessee 38163, USA
| | - Horrick Sharma
- Department of Pharmaceutical Sciences, College of Pharmacy, University of Tennessee Health Science Center, Memphis, Tennessee 38163, USA
| | - Ming-Hai Wang
- 1] Cancer Biology Center, School of Pharmacy, Texas Tech University Health Sciences Center, Amarillo, Texas 79106, USA [2] Department of Biomedical Sciences, School of Pharmacy, Texas Tech University Health Sciences Center, Amarillo, Texas 79106, USA
| | - Hui Wang
- Key Laboratory of Food Safety Research Center, Institute for Nutritional Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai 200031, China
| | - John K Buolamwini
- Department of Pharmaceutical Sciences, College of Pharmacy, University of Tennessee Health Science Center, Memphis, Tennessee 38163, USA
| | - Ruiwen Zhang
- 1] Department of Pharmaceutical Sciences, School of Pharmacy, Texas Tech University Health Sciences Center, Amarillo, Texas 79106, USA [2] Cancer Biology Center, School of Pharmacy, Texas Tech University Health Sciences Center, Amarillo, Texas 79106, USA
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Mardekian SK, Solomides CC, Gong JZ, Peiper SC, Wang ZX, Bajaj R. Comparison of Chromogenic In Situ Hybridization and Fluorescence In Situ Hybridization for the Evaluation of MDM2 Amplification in Adipocytic Tumors. J Clin Lab Anal 2014; 29:462-8. [PMID: 25132285 DOI: 10.1002/jcla.21794] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/10/2014] [Accepted: 06/12/2014] [Indexed: 11/08/2022] Open
Abstract
BACKGROUND Atypical lipomatous tumor/well-differentiated liposarcoma (ALT-WDLPS) and dedifferentiated liposarcoma (DDLPS) are characterized cytogenetically by a 12q13-15 amplification involving the mouse double minute 2 (MDM2) oncogene. Fluorescence in situ hybridization (FISH) is used frequently to detect this amplification and aid with the diagnosis of these entities, which is difficult by morphology alone. Recently, bright-field in situ hybridization techniques such as chromogenic in situ hybridization (CISH) have been introduced for the determination of MDM2 amplification status. METHODS The present study compared the results of FISH and CISH for detecting MDM2 amplification in 41 cases of adipocytic tumors. Amplification was defined in both techniques as a MDM2/CEN12 ratio of 2 or greater. RESULTS Eleven cases showed amplification with both FISH and CISH, and 26 cases showed no amplification with both methods. Two cases had discordant results between CISH and FISH, and two cases were not interpretable by CISH. CONCLUSION CISH is advantageous for allowing pathologists to evaluate the histologic and molecular alterations occurring simultaneously in a specimen. Moreover, CISH is found to be more cost- and time-efficient when used with automation, and the signals do not quench over time. CISH technique is a reliable alternative to FISH in the evaluation of adipocytic tumors for MDM2 amplification.
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Affiliation(s)
- Stacey K Mardekian
- Department of Pathology, Anatomy and Cell Biology, Thomas Jefferson University, Philadelphia, Pennsylvania
| | - Charalambos C Solomides
- Department of Pathology, Anatomy and Cell Biology, Thomas Jefferson University, Philadelphia, Pennsylvania
| | - Jerald Z Gong
- Department of Pathology, Anatomy and Cell Biology, Thomas Jefferson University, Philadelphia, Pennsylvania
| | - Stephen C Peiper
- Department of Pathology, Anatomy and Cell Biology, Thomas Jefferson University, Philadelphia, Pennsylvania
| | - Zi-Xuan Wang
- Department of Pathology, Anatomy and Cell Biology, Thomas Jefferson University, Philadelphia, Pennsylvania
| | - Renu Bajaj
- Department of Pathology, Anatomy and Cell Biology, Thomas Jefferson University, Philadelphia, Pennsylvania
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Snoek BC, Wilt LHAMD, Jansen G, Peters GJ. Role of E3 ubiquitin ligases in lung cancer. World J Clin Oncol 2013; 4:58-69. [PMID: 23936758 PMCID: PMC3708064 DOI: 10.5306/wjco.v4.i3.58] [Citation(s) in RCA: 26] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/03/2012] [Revised: 01/10/2013] [Accepted: 06/06/2013] [Indexed: 02/06/2023] Open
Abstract
E3 ubiquitin ligases are a large family of proteins that catalyze the ubiquitination of many protein substrates for targeted degradation by the 26S proteasome. Therefore, E3 ubiquitin ligases play an essential role in a variety of biological processes including cell cycle regulation, proliferation and apoptosis. E3 ubiquitin ligases are often found overexpressed in human cancers, including lung cancer, and their deregulation has been shown to contribute to cancer development. However, the lack of specific inhibitors in clinical trials is a major issue in targeting E3 ubiquitin ligases with currently only one E3 ubiquitin ligase inhibitor being tested in the clinical setting. In this review, we focus on E3 ubiquitin ligases that have been found deregulated in lung cancer. Furthermore, we discuss the processes in which they are involved and evaluate them as potential anti-cancer targets. By better understanding the mechanisms by which E3 ubiquitin ligases regulate biological processes and their exact role in carcinogenesis, we can improve the development of specific E3 ubiquitin ligase inhibitors and pave the way for novel treatment strategies for cancer patients.
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Nag S, Qin J, Srivenugopal KS, Wang M, Zhang R. The MDM2-p53 pathway revisited. J Biomed Res 2013; 27:254-71. [PMID: 23885265 PMCID: PMC3721034 DOI: 10.7555/jbr.27.20130030] [Citation(s) in RCA: 233] [Impact Index Per Article: 19.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/15/2013] [Accepted: 04/12/2013] [Indexed: 12/15/2022] Open
Abstract
The p53 tumor suppressor is a key transcription factor regulating cellular pathways such as DNA repair, cell cycle, apoptosis, angiogenesis, and senescence. It acts as an important defense mechanism against cancer onset and progression, and is negatively regulated by interaction with the oncoprotein MDM2. In human cancers, the TP53 gene is frequently mutated or deleted, or the wild-type p53 function is inhibited by high levels of MDM2, leading to downregulation of tumor suppressive p53 pathways. Thus, the inhibition of MDM2-p53 interaction presents an appealing therapeutic strategy for the treatment of cancer. However, recent studies have revealed the MDM2-p53 interaction to be more complex involving multiple levels of regulation by numerous cellular proteins and epigenetic mechanisms, making it imperative to reexamine this intricate interplay from a holistic viewpoint. This review aims to highlight the multifaceted network of molecules regulating the MDM2-p53 axis to better understand the pathway and exploit it for anticancer therapy.
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Affiliation(s)
- Subhasree Nag
- Department of Pharmaceutical Sciences, School of Pharmacy, Texas Tech University Health Sciences Center, Amarillo, TX 79106, USA
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Sosin AM, Burger AM, Siddiqi A, Abrams J, Mohammad RM, Al-Katib AM. HDM2 antagonist MI-219 (spiro-oxindole), but not Nutlin-3 (cis-imidazoline), regulates p53 through enhanced HDM2 autoubiquitination and degradation in human malignant B-cell lymphomas. J Hematol Oncol 2012; 5:57. [PMID: 22989009 PMCID: PMC3473265 DOI: 10.1186/1756-8722-5-57] [Citation(s) in RCA: 30] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/22/2012] [Accepted: 09/01/2012] [Indexed: 01/10/2023] Open
Abstract
Background Lymphomas frequently retain wild-type (wt) p53 function but overexpress HDM2, thereby compromising p53 activity. Therefore, lymphoma is a suitable model for studying the therapeutic value of disrupting the HDM2-p53 interaction by small-molecule inhibitors (SMIs). HDM2 have been developed and are under various stages of preclinical and clinical investigation. Previously, we examined the anti-lymphoma activity of MI-319, the laboratory grade of a new class of HDM2 SMI, the spiro-oxindole, in follicular lymphoma. Since then, MI-219, the clinical grade has become readily available. This study further examines the preclinical effects and mechanisms of MI-219 in a panel of human lymphoma cell lines as well as a cohort of patient-derived B-lymphcytes for its potential clinical use. Results Preclinical assessment of MI-219 was evaluated by means of an in vitro and ex vivo approach and compared to Nutlin-3, the gold standard. Characterization of p53 activity and stability were assessed by quantitative PCR, Western blot, and immunoprecipitation. Biological outcome was measured using Trypan blue exclusion assay, Annexin V/PI, PARP and caspase-3 cleavage. Surprisingly, the overall biological effects of Nutlin-3 were more delayed (48 h) while MI-219 triggered an earlier response (12-24 h), predominantly in the form of apoptotic cell death. Using a cell free autoubiquitination assay, neither agent interfered with HDM2 E3 ligase function. MI-219 was more effective in upregulating wt-p53 stabilization compared to Nutlin-3. MI-219, but not Nutlin-3, enhanced the autoubiquitination and degradation of HDM2. Conclusions Our data reveals unexpected differences between MI-219 and the well-studied Nutlin-3 in lymphoma cell lines and patient samples. We suggest a novel mechanism for MI-219 that alters the functional activity of HDM2 through enhanced autoubiquitination and degradation. Additionally, this mechanism appears to correspond to biological outcome. Our results provide evidence that different classes of HDM2 SMIs elicit molecular events that extend beyond HDM2-p53 dissociation which may be of biological and potentially therapeutic importance.
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Affiliation(s)
- Angela M Sosin
- Department of Oncology, Barbara Ann Karmanos Cancer Institute (KCI), Detroit, MI 48201, USA
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Wang W, Zhang X, Qin JJ, Voruganti S, Nag SA, Wang MH, Wang H, Zhang R. Natural product ginsenoside 25-OCH3-PPD inhibits breast cancer growth and metastasis through down-regulating MDM2. PLoS One 2012; 7:e41586. [PMID: 22911819 PMCID: PMC3402429 DOI: 10.1371/journal.pone.0041586] [Citation(s) in RCA: 63] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/06/2012] [Accepted: 06/26/2012] [Indexed: 01/04/2023] Open
Abstract
Although ginseng and related herbs have a long history of utility for various health benefits, their application in cancer therapy and underlying mechanisms of action are not fully understood. Our recent work has shown that 20(S)-25-methoxyl-dammarane-3β, 12β, 20-triol (25-OCH3-PPD), a newly identified ginsenoside from Panax notoginseng, exerts activities against a variety of cancer cells in vitro and in vivo. This study was designed to investigate its anti-breast cancer activity and the underlying mechanisms of action. We observed that 25-OCH3-PPD decreased the survival of breast cancer cells by induction of apoptosis and G1 phase arrest and inhibited the growth of breast cancer xenografts in vivo. We further demonstrated that, in a dose- and time-dependent manner, 25-OCH3-PPD inhibited MDM2 expression at both transcriptional and post-translational levels in human breast cancer cells with various p53 statuses (wild type and mutant). Moreover, 25-OCH3-PPD inhibited in vitro cell migration, reduced the expression of epithelial-to-mesenchymal transition (EMT) markers, and prevented in vivo metastasis of breast cancer. In summary, 25-OCH3-PPD is a potential therapeutic and anti-metastatic agent for human breast cancer through down-regulating MDM2. Further preclinical and clinical development of this agent is warranted.
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Affiliation(s)
- Wei Wang
- Department of Pharmaceutical Sciences, School of Pharmacy, Texas Tech University Health Sciences Center, Amarillo, Texas, United States of America
- Cancer Biology Center, School of Pharmacy, Texas Tech University Health Sciences Center, Amarillo, Texas, United States of America
| | - Xu Zhang
- Department of Pharmaceutical Sciences, School of Pharmacy, Texas Tech University Health Sciences Center, Amarillo, Texas, United States of America
| | - Jiang-Jiang Qin
- Department of Pharmaceutical Sciences, School of Pharmacy, Texas Tech University Health Sciences Center, Amarillo, Texas, United States of America
| | - Sukesh Voruganti
- Department of Pharmaceutical Sciences, School of Pharmacy, Texas Tech University Health Sciences Center, Amarillo, Texas, United States of America
| | - Subhasree Ashok Nag
- Department of Pharmaceutical Sciences, School of Pharmacy, Texas Tech University Health Sciences Center, Amarillo, Texas, United States of America
| | - Ming-Hai Wang
- Cancer Biology Center, School of Pharmacy, Texas Tech University Health Sciences Center, Amarillo, Texas, United States of America
- Department of Biomedical Sciences, School of Pharmacy, Texas Tech University Health Sciences Center, Amarillo, Texas, United States of America
| | - Hui Wang
- Institute for Nutritional Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai, China
| | - Ruiwen Zhang
- Department of Pharmaceutical Sciences, School of Pharmacy, Texas Tech University Health Sciences Center, Amarillo, Texas, United States of America
- Cancer Biology Center, School of Pharmacy, Texas Tech University Health Sciences Center, Amarillo, Texas, United States of America
- * E-mail:
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Chasapis CT, Loutsidou AC, Spiliopoulou CA, Stefanidou ME. Zinc and human health: an update. Arch Toxicol 2011; 86:521-34. [PMID: 22071549 DOI: 10.1007/s00204-011-0775-1] [Citation(s) in RCA: 567] [Impact Index Per Article: 40.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/18/2011] [Accepted: 10/26/2011] [Indexed: 02/07/2023]
Abstract
The importance of micronutrients in health and nutrition is undisputable, and among them, zinc is an essential element whose significance to health is increasingly appreciated and whose deficiency may play an important role in the appearance of diseases. Zinc is one of the most important trace elements in the organism, with three major biological roles, as catalyst, structural, and regulatory ion. Zinc-binding motifs are found in many proteins encoded by the human genome physiologically, and free zinc is mainly regulated at the single-cell level. Zinc has critical effect in homeostasis, in immune function, in oxidative stress, in apoptosis, and in aging, and significant disorders of great public health interest are associated with zinc deficiency. In many chronic diseases, including atherosclerosis, several malignancies, neurological disorders, autoimmune diseases, aging, age-related degenerative diseases, and Wilson's disease, the concurrent zinc deficiency may complicate the clinical features, affect adversely immunological status, increase oxidative stress, and lead to the generation of inflammatory cytokines. In these diseases, oxidative stress and chronic inflammation may play important causative roles. It is therefore important that status of zinc is assessed in any case and zinc deficiency is corrected, since the unique properties of zinc may have significant therapeutic benefits in these diseases. In the present paper, we review the zinc as a multipurpose trace element, its biological role in homeostasis, proliferation and apoptosis and its role in immunity and in chronic diseases, such as cancer, diabetes, depression, Wilson's disease, Alzheimer's disease, and other age-related diseases.
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Affiliation(s)
- Christos T Chasapis
- Department of Pharmacy, School of Health Sciences, University of Patras, Patras, Greece
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Dujardin F, Binh MBN, Bouvier C, Gomez-Brouchet A, Larousserie F, Muret AD, Louis-Brennetot C, Aurias A, Coindre JM, Guillou L, Pedeutour F, Duval H, Collin C, de Pinieux G. MDM2 and CDK4 immunohistochemistry is a valuable tool in the differential diagnosis of low-grade osteosarcomas and other primary fibro-osseous lesions of the bone. Mod Pathol 2011; 24:624-37. [PMID: 21336260 DOI: 10.1038/modpathol.2010.229] [Citation(s) in RCA: 136] [Impact Index Per Article: 9.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/05/2023]
Abstract
Low-grade osteosarcoma is a rare malignancy that may be subdivided into two main subgroups on the basis of location in relation to the bone cortex, that is, parosteal osteosarcoma and low-grade central osteosarcoma. Their histological appearance is quite similar and characterized by spindle cell stroma with low-to-moderate cellularity and well-differentiated anastomosing bone trabeculae. Low-grade osteosarcomas have a simple genetic profile with supernumerary ring chromosomes comprising amplification of chromosome 12q13-15, including the cyclin-dependent kinase 4 (CDK4) and murine double-minute type 2 (MDM2) gene region. Low-grade osteosarcoma can be confused with fibrous and fibro-osseous lesions such as fibromatosis and fibrous dysplasia on radiological and histological findings. We investigated MDM2-CDK4 immunohistochemical expression in a series of 72 low-grade osteosarcomas and 107 fibrous or fibro-osseous lesions of the bone or paraosseous soft tissue. The MDM2-CDK4 amplification status of low-grade osteosarcoma was also evaluated by comparative genomic hybridization array in 18 cases, and the MDM2 amplification status was evaluated by fluorescence in situ hybridization or quantitative real-time polymerase chain reaction in 31 cases of benign fibrous and fibro-osseous lesions. MDM2-CDK4 immunostaining and MDM2 amplification by fluorescence in situ hybridization or quantitative real-time polymerase chain reaction were investigated in a control group of 23 cases of primary high-grade bone sarcoma, including 20 conventional high-grade osteosarcomas, two pleomorphic spindle cell sarcomas/malignant fibrous histiocytomas and one leiomyosarcoma. The results showed that MDM2 and/or CDK4 immunoreactivity was present in 89% of low-grade osteosarcoma specimens. All benign fibrous and fibro-osseous lesions and the tumors of the control group were negative for MDM2 and CDK4. These results were consistent with the MDM2 and CDK4 amplification results. In conclusion, immunohistochemical expression of MDM2 and CDK4 is specific and provides sensitive markers for the diagnosis of low-grade osteosarcomas, helping to differentiate them from benign fibrous and fibro-osseous lesions, particularly in cases with atypical radio-clinical presentation and/or limited biopsy samples.
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Affiliation(s)
- Fanny Dujardin
- Department of Pathology, Trousseau University Hospital and University François Rabelais, Tours Cedex 9, France
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Ali I, Penttinen-Damdimopoulou PE, Mäkelä SI, Berglund M, Stenius U, Åkesson A, Håkansson H, Halldin K. Estrogen-like effects of cadmium in vivo do not appear to be mediated via the classical estrogen receptor transcriptional pathway. ENVIRONMENTAL HEALTH PERSPECTIVES 2010; 118:1389-94. [PMID: 20525538 PMCID: PMC2957917 DOI: 10.1289/ehp.1001967] [Citation(s) in RCA: 61] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 01/19/2010] [Accepted: 06/04/2010] [Indexed: 05/25/2023]
Abstract
BACKGROUND Cadmium (Cd), a ubiquitous food contaminant, has been proposed to be an endocrine disruptor by inducing estrogenic responses in vivo. Several in vitro studies suggested that these effects are mediated via estrogen receptors (ERs). OBJECTIVE We performed this study to clarify whether Cd-induced effects in vivo are mediated via classical ER signaling through estrogen responsive element (ERE)-regulated genes or if other signaling pathways are involved. METHODS We investigated the estrogenic effects of cadmium chloride (CdCl2) exposure in vivo by applying the Organisation for Economic Co-operation and Development (OECD) rodent uterotrophic bioassay to transgenic ERE-luciferase reporter mice. Immature female mice were injected subcutaneously with CdCl2 (5, 50, or 500 µg/kg body weight) or with 17α-ethinylestradiol (EE2) on 3 consecutive days. We examined uterine weight and histology, vaginal opening, body and organ weights, Cd tissue retention, activation of mitogen-activated protein kinase (MAPK) pathways, and ERE-dependent luciferase expression. RESULTS CdCl2 increased the height of the uterine luminal epithelium in a dose-dependent manner without increasing the uterine wet weight, altering the timing of vaginal opening, or affecting the luciferase activity in reproductive or nonreproductive organs. However, we observed changes in the phosphorylation of mouse double minute 2 oncoprotein (Mdm2) and extracellular signal-regulated kinase (Erk1/2) in the liver after CdCl2 exposure. As we expected, EE2 advanced vaginal opening and increased uterine epithelial height, uterine wet weight, and luciferase activity in various tissues. CONCLUSION Our data suggest that Cd exposure induces a limited spectrum of estrogenic responses in vivo and that, in certain targets, effects of Cd might not be mediated via classical ER signaling through ERE-regulated genes.
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Affiliation(s)
- Imran Ali
- Institute of Environmental Medicine, Karolinska Institutet, Stockholm, Sweden
| | | | - Sari I. Mäkelä
- Functional Foods Forum and Institute of Biomedicine, University of Turku, Turku, Finland
| | - Marika Berglund
- Institute of Environmental Medicine, Karolinska Institutet, Stockholm, Sweden
| | - Ulla Stenius
- Institute of Environmental Medicine, Karolinska Institutet, Stockholm, Sweden
| | - Agneta Åkesson
- Institute of Environmental Medicine, Karolinska Institutet, Stockholm, Sweden
| | - Helen Håkansson
- Institute of Environmental Medicine, Karolinska Institutet, Stockholm, Sweden
| | - Krister Halldin
- Institute of Environmental Medicine, Karolinska Institutet, Stockholm, Sweden
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Hispolon promotes MDM2 downregulation through chaperone-mediated autophagy. Biochem Biophys Res Commun 2010; 398:26-31. [PMID: 20540933 DOI: 10.1016/j.bbrc.2010.06.004] [Citation(s) in RCA: 33] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/27/2010] [Accepted: 06/01/2010] [Indexed: 11/21/2022]
Abstract
Amplification and overexpression of murine double minute (MDM2) has been observed in several human cancers. Some chemotherapeutic agents cause MDM2 ubiquitination and degradation in a proteasome-dependent system. In addition to the proteasome system, chaperone-mediated autophagy (CMA) is a lysosomal pathway for selective misfolded protein degradation. Molecular chaperone heat shock cognate 70 protein (Hsc70) recognizes the misfolded proteins, which are then delivered to lysosome-associated membrane protein type 2A (LAMP2A) for lysosomal degradation. Our previous study reported that hispolon was able to induce cell apoptosis and downregulate MDM2 expression. In this study, our results showed that the proteasome inhibitor, MG132, could not inhibit hispolon-induced MDM2 downregulation. In contrast, both inhibition of lysosomes with NH(4)Cl and inhibition of LAMP2A using siRNA partially attenuated hispolon-induced MDM2 downregulation. To determine whether Hsc70 recognizes MDM2 on amino acids 135-141, SMP14 antibody was used to compete with Hsc70 for interaction with MDM2. After Hsc70 knockdown, SMP14 antibody immunoprecipitated increased MDM2. We also found that hispolon induced increased association of Hsp70, Hsc70, Hsp90 and LAMP2A with MDM2. This association was inhibited in cells pretreated with geldanamycin (GA), an Hsp90 inhibitor. GA also attenuated hispolon-induced MDM2 downregulation. Meanwhile, inhibition of Hsc70 using siRNA attenuated hispolon-induced MDM2 downregulation. Our study provides the first example of the ability of hispolon to mediate MDM2 downregulation in lysosomes through the CMA pathway.
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Wang YL, Qian WJ, Wei WG, Zhang Y, Yao ZJ. Synthesis of the cyclic nonapeptide of chlorofusin using a convergent [3+3+3]-fragment coupling strategy. Tetrahedron 2010. [DOI: 10.1016/j.tet.2010.03.032] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/19/2022]
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Ku WC, Chiu SK, Chen YJ, Huang HH, Wu WG, Chen YJ. Complementary quantitative proteomics reveals that transcription factor AP-4 mediates E-box-dependent complex formation for transcriptional repression of HDM2. Mol Cell Proteomics 2009; 8:2034-50. [PMID: 19505873 PMCID: PMC2742435 DOI: 10.1074/mcp.m900013-mcp200] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/01/2009] [Revised: 05/26/2009] [Indexed: 01/13/2023] Open
Abstract
Transcription factor activating enhancer-binding protein 4 (AP-4) is a basic helix-loop-helix protein that binds to E-box elements. AP-4 has received increasing attention for its regulatory role in cell growth and development, including transcriptional repression of the human homolog of murine double minute 2 (HDM2), an important oncoprotein controlling cell growth and survival, by an unknown mechanism. Here we demonstrate that AP-4 binds to an E-box located in the HDM2-P2 promoter and represses HDM2 transcription in a p53-independent manner. Incremental truncations of AP-4 revealed that the C-terminal Gln/Pro-rich domain was essential for transcriptional repression of HDM2. To further delineate the molecular mechanism(s) of AP-4 transcriptional control and its potential implications, we used DNA-affinity purification followed by complementary quantitative proteomics, cICAT and iTRAQ labeling methods, to identify a previously unknown E-box-bound AP-4 protein complex containing 75 putative components. The two labeling methods complementarily quantified differentially AP-4-enriched proteins, including the most significant recruitment of DNA damage response proteins, followed by transcription factors, transcriptional repressors/corepressors, and histone-modifying proteins. Specific interaction of AP-4 with CCCTC binding factor, stimulatory protein 1, and histone deacetylase 1 (an AP-4 corepressor) was validated using AP-4 truncation mutants. Importantly, inclusion of trichostatin A did not alleviate AP-4-mediated repression of HDM2 transcription, suggesting a previously unidentified histone deacetylase-independent repression mechanism. In contrast, the complementary quantitative proteomics study suggested that transcription repression occurs via coordination of AP-4 with other transcription factors, histone methyltransferases, and/or a nucleosome remodeling SWI.SNF complex. In addition to previously known functions of AP-4, our data suggest that AP-4 participates in a transcriptional-regulating complex at the HDM2-P2 promoter in response to DNA damage.
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Affiliation(s)
- Wei-Chi Ku
- From the ‡Chemical Biology and Molecular Biophysics Program, Taiwan International Graduate Program, Institute of Chemistry, Academia Sinica, Taipei 115, Taiwan
- §Institute of Bioinformatics and Structural Biology, National Tsing Hua University, Hsinchu 300, Taiwan
| | - Sung-Kay Chiu
- ¶Department of Biology and Chemistry, City University of Hong Kong, Hong Kong, China
| | - Yi-Ju Chen
- ‖Institute of Biochemical Sciences, National Taiwan University, Taipei 106, Taiwan
| | - Hsin-Hung Huang
- ‖Institute of Biochemical Sciences, National Taiwan University, Taipei 106, Taiwan
| | - Wen-Guey Wu
- From the ‡Chemical Biology and Molecular Biophysics Program, Taiwan International Graduate Program, Institute of Chemistry, Academia Sinica, Taipei 115, Taiwan
- §Institute of Bioinformatics and Structural Biology, National Tsing Hua University, Hsinchu 300, Taiwan
| | - Yu-Ju Chen
- From the ‡Chemical Biology and Molecular Biophysics Program, Taiwan International Graduate Program, Institute of Chemistry, Academia Sinica, Taipei 115, Taiwan
- **Genomics Research Center, Academia Sinica, Taipei 115, Taiwan, and
- ‡‡Department of Chemistry, National Taiwan University, Taipei 106, Taiwan
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Clark RC, Lee SY, Hwang I, Searcey M, Boger DL. Evaluation of Chlorofusin, its Seven Chromophore Diastereomers, and Key Analogues. Tetrahedron Lett 2009; 50:3151-3153. [PMID: 20161293 DOI: 10.1016/j.tetlet.2009.01.081] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/10/2023]
Abstract
Chlorofusin, its seven chromophore diastereomers, and key analogues were comparatively examined for inhibition of MDM2-p53 binding revealing that the chromophore, but not simple replacements, contributes significantly to the natural products properties, and that this contribution is independent of its relative and absolute stereochemistry.
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Affiliation(s)
- Ryan C Clark
- Department of Chemistry and the Skaggs Institute for Chemical Biology, The Scripps Research Institute, 10550 N. Torrey Pines Road, La Jolla, California 92037, USA
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Soucy TA, Smith PG, Rolfe M. Targeting NEDD8-activated cullin-RING ligases for the treatment of cancer. Clin Cancer Res 2009; 15:3912-6. [PMID: 19509147 DOI: 10.1158/1078-0432.ccr-09-0343] [Citation(s) in RCA: 187] [Impact Index Per Article: 11.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
Abstract
E3 ubiquitin ligases regulate many dynamic cellular processes important for cancer cell survival. Together with ubiquitin-activating enzyme (E1) and ubiquitin-conjugating enzymes (E2s), E3s catalyze the ubiquitination of numerous protein substrates that are subsequently targeted to the 26S proteasome for degradation. The clinical success of the proteasome inhibitor bortezomib has encouraged the evaluation of other components of the ubiquitin proteasome system for pharmaceutical intervention. Targeting specific E3s is particularly attractive because there is the potential to selectively block the degradation of certain cellular proteins and possibly avoid unwanted effects on other proteins. The cullin-RING ubiquitin E3 ligases (CRLs) represent the largest subfamily of E3s. The requirement that CRLs be activated by NEDD8 modification on the cullin protein offers an "achilles heel" for modulating this entire subfamily. NEDD8-activating enzyme (NAE) catalyzes the first step in the NEDD8 pathway and as such controls the activity of CRLs. In this article, we describe the role of the NEDD8 pathway in activating CRLs and discuss the preclinical findings with a first-in-class NAE inhibitor that is currently in phase I clinical trials for both solid tumor and hematological malignancies. In addition, we speculate where NAE inhibitors may find clinical utility.
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Affiliation(s)
- Teresa A Soucy
- Discovery, Millennium Pharmaceuticals, Inc, Cambridge, Massachusetts 02139, USA.
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Renouf B, Hollville E, Pujals A, Tétaud C, Garibal J, Wiels J. Activation of p53 by MDM2 antagonists has differential apoptotic effects on Epstein-Barr virus (EBV)-positive and EBV-negative Burkitt's lymphoma cells. Leukemia 2009; 23:1557-63. [PMID: 19421231 DOI: 10.1038/leu.2009.92] [Citation(s) in RCA: 23] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/23/2023]
Abstract
p53 inactivation is often observed in Burkitt's lymphoma (BL) cells, because of either mutations in p53 gene or an overexpression of the p53-negative regulator MDM2. Epstein-Barr virus (EBV) is present in virtually 100% of BL cases occurring in endemic areas, but in only 10-20% of sporadic cases. In EBV(-) BL cells, reactivation of p53, induced by reducing MDM2 protein level, led to apoptosis. We show here that nutlin-3, a potent antagonist of MDM2, activates the p53 pathway in all BL cell lines harboring wild-type p53, regardless of EBV status. However, nutlin-3 strongly induced apoptosis in EBV(-) or latency I EBV(+) cells, whereas latency III EBV(+) cells were much more resistant. Prior treatment with sublethal doses of nutlin-3 sensitizes EBV(-) or latency I EBV(+) cells to apoptosis induced by etoposide or melphalan, but protects latency III EBV(+) cells. p21(WAF1) which is overexpressed in the latter, is involved in this protective effect, as siRNA-mediated inhibition of p21(WAF1) restores sensitivity to etoposide. Nutlin-3 protects latency III BL cells by inducing a p21(WAF1)-mediated G1 arrest. Most BL patients with wild-type p53 tumors could therefore benefit from treatment with nutlin-3, after a careful determination of the latency pattern of EBV in infected patients.
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Affiliation(s)
- B Renouf
- UMR 8126 CNRS, Univ Paris-Sud, Institut Gustave Roussy, Villejuif, France
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