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Salas-Escabillas DJ, Hoffman MT, Brender SM, Moore JS, Wen HJ, Benitz S, Davis ET, Long D, Wombwell AM, Chianis ERD, Allen-Petersen BL, Steele NG, Sears RC, Matsumoto I, DelGiorno KE, Crawford HC. Tuft cells transdifferentiate to neural-like progenitor cells in the progression of pancreatic cancer. Dev Cell 2025; 60:837-852.e3. [PMID: 39721583 DOI: 10.1016/j.devcel.2024.12.003] [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: 04/19/2024] [Revised: 09/13/2024] [Accepted: 12/02/2024] [Indexed: 12/28/2024]
Abstract
Pancreatic ductal adenocarcinoma (PDA) is partly initiated through the transdifferentiation of acinar cells to metaplasia, which progresses to neoplasia and cancer. Tuft cells (TCs) are chemosensory cells not found in the normal pancreas but arise in cancer precursor lesions and diminish during progression to carcinoma. These metaplastic TCs (mTCs) suppress tumor progression through communication with the tumor microenvironment, but their fate during progression is unknown. To determine the fate of mTCs during PDA progression, we created a dual recombinase lineage trace model, wherein a pancreas-specific FlpO was used to induce tumorigenesis, while a tuft-cell specific Pou2f3CreERT/+ driver was used to induce expression of a tdTomato reporter. We found that mTCs in carcinoma transdifferentiate into neural-like progenitor cells (NRPs), a cell type associated with poor survival in patients. Using conditional knockout and overexpression systems, we found that Myc activity in mTCs is necessary and sufficient to induce this tuft-to-neuroendocrine transition (TNT).
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Affiliation(s)
- Daniel J Salas-Escabillas
- Cancer Biology, University of Michigan, Ann Arbor, MI, USA; Department of Surgery, Henry Ford Health, Detroit, MI, USA; Department of Pharmacology and Toxicology, Michigan State University, Lansing, MI, USA
| | - Megan T Hoffman
- Department of Molecular and Integrative Physiology, University of Michigan, Ann Arbor, MI, USA
| | - Sydney M Brender
- Department of Surgery, Henry Ford Health, Detroit, MI, USA; Department of Pharmacology and Toxicology, Michigan State University, Lansing, MI, USA
| | - Jacee S Moore
- Department of Surgery, Henry Ford Health, Detroit, MI, USA; Department of Pharmacology and Toxicology, Michigan State University, Lansing, MI, USA
| | - Hui-Ju Wen
- Department of Surgery, Henry Ford Health, Detroit, MI, USA; Department of Pharmacology and Toxicology, Michigan State University, Lansing, MI, USA
| | - Simone Benitz
- Department of Surgery, Henry Ford Health, Detroit, MI, USA; Department of Pharmacology and Toxicology, Michigan State University, Lansing, MI, USA
| | - Erick T Davis
- Department of Surgery, Henry Ford Health, Detroit, MI, USA; Department of Pharmacology and Toxicology, Michigan State University, Lansing, MI, USA
| | - Daniel Long
- Department of Surgery, Henry Ford Health, Detroit, MI, USA; Department of Pharmacology and Toxicology, Michigan State University, Lansing, MI, USA
| | - Allison M Wombwell
- Department of Surgery, Henry Ford Health, Detroit, MI, USA; Department of Pharmacology and Toxicology, Michigan State University, Lansing, MI, USA
| | - Ella Rose D Chianis
- Department of Biological Sciences, Purdue University, West Lafayette, IN, USA
| | | | - Nina G Steele
- Department of Surgery, Henry Ford Health, Detroit, MI, USA; Department of Pharmacology and Toxicology, Michigan State University, Lansing, MI, USA
| | - Rosalie C Sears
- Department of Molecular and Medical Genetics, Oregon Health & Science University, Portland, OR, USA
| | | | - Kathleen E DelGiorno
- Department of Cell and Developmental Biology, Vanderbilt University School of Medicine, Nashville, TN, USA
| | - Howard C Crawford
- Department of Surgery, Henry Ford Health, Detroit, MI, USA; Department of Pharmacology and Toxicology, Michigan State University, Lansing, MI, USA.
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Edaibis R, Akel R, Shin JA. Beyond small molecules: advancing MYC-targeted cancer therapies through protein engineering. Transcription 2025; 16:67-85. [PMID: 39878458 PMCID: PMC11970745 DOI: 10.1080/21541264.2025.2453315] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/03/2024] [Revised: 01/08/2025] [Accepted: 01/09/2025] [Indexed: 01/31/2025] Open
Abstract
Protein engineering has emerged as a powerful approach toward the development of novel therapeutics targeting the MYC/MAX/E-box network, an active driver of >70% of cancers. The MYC/MAX heterodimer regulates numerous genes in our cells by binding the Enhancer box (E-box) DNA site and activating the transcription of downstream genes. Traditional small molecules that inhibit MYC face significant limitations that include toxic effects, drug delivery challenges, and resistance. Recent advances in protein engineering offer promising alternatives by creating protein-based drugs that directly disrupt the MYC/MAX dimerization interface and/or MYC/MAX's binding to specific DNA targets. Designed DNA binding proteins like Omomyc, DuoMyc, ME47, MEF, and Mad inhibit MYC activity through specific dimerization, sequestration, and DNA-binding mechanisms. Compared to small molecules, these engineered proteins can offer superior specificity and efficacy and provide a potential pathway for overcoming the limitations of traditional cancer therapies. The success of these protein therapeutics highlights the importance of protein engineering in developing cancer treatments.
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Affiliation(s)
- Rama Edaibis
- Department of Chemistry, University of Toronto, Mississauga, ON, Canada
| | - Raneem Akel
- Department of Chemistry, University of Toronto, Mississauga, ON, Canada
| | - Jumi A. Shin
- Department of Chemistry, University of Toronto, Mississauga, ON, Canada
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Ai Z, Li D, Lan S, Zhang C. Nanomaterials exert biological effects by influencing the ubiquitin-proteasome system. Eur J Med Chem 2025; 282:116974. [PMID: 39556894 DOI: 10.1016/j.ejmech.2024.116974] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/03/2024] [Revised: 10/05/2024] [Accepted: 10/14/2024] [Indexed: 11/20/2024]
Abstract
The ubiquitin-proteasome system (UPS) is an important type of protein post-translational modification that affects the quantity and quality of various proteins and influences cellular processes such as the cell cycle, transcription, oxidative stress, and autophagy. Nanomaterials (NMs), which exhibit excellent physicochemical properties, can directly interact with the UPS and act as molecular-targeted drugs to induce changes in biological processes. This review provides an overview of the influence of NMs on the UPS of misfolded proteins and key proteins, which are related to cancer, neurodegenerative diseases and oxidative stress. This review also summarizes the role of modification processes involved in ubiquitination the biological effects of NMs and the mechanism of such effects of NMs through regulation of the UPS. This review deepens our understanding of the influence of NMs on the protein degradation process and provides new potential therapeutic targets for disease.
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Affiliation(s)
- Zhen Ai
- Stomatological Hospital, School of Stomatology, Southern Medical University, Guangzhou, 510280, China
| | - Dan Li
- Stomatological Hospital, School of Stomatology, Southern Medical University, Guangzhou, 510280, China
| | - Shuquan Lan
- Stomatological Hospital, School of Stomatology, Southern Medical University, Guangzhou, 510280, China
| | - Chao Zhang
- Stomatological Hospital, School of Stomatology, Southern Medical University, Guangzhou, 510280, China.
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Li W, Yang C, Cheng Z, Wu Y, Zhou S, Qi X, Zhang Y, Hu J, Xie M, Chen C. Gallium complex K6 inhibits colorectal cancer by increasing ROS levels to induce DNA damage and enhance phosphatase and tensin homolog activity. MedComm (Beijing) 2024; 5:e665. [PMID: 39049965 PMCID: PMC11266899 DOI: 10.1002/mco2.665] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/31/2023] [Revised: 06/20/2024] [Accepted: 06/21/2024] [Indexed: 07/27/2024] Open
Abstract
Colorectal cancer (CRC) is one of the most common malignancies worldwide. In the clinical realm, platinum-based drugs hold an important role in the chemotherapy of CRC. Nonetheless, a multitude of patients, due to tumor protein 53 (TP53) gene mutations, experience the emergence of drug resistance. This phenomenon gravely impairs the effectiveness of therapy and long-term prognosis. Gallium, a metallic element akin to iron, has been reported that has the potential to be used to develop new metal anticancer drugs. In this study, we screened and established the gallium complex K6 as a potent antitumor agent in both in vitro and in vivo. K6 exhibited superior efficacy in impeding the growth, proliferation, and viability of CRC cells carrying TP53 mutations compared to oxaliplatin. Mechanistically, K6 escalated reactive oxygen species levels and led deoxyribonucleic acid (DNA) damage. Furthermore, K6 effectively suppressed the phosphoinositide 3-kinase (PI3K)/protein kinase B (PKB)/glycogen synthase kinase 3 beta (GSK3β) pathway, leading to the degradation of its downstream effectors myelocytomatosis (c-Myc) and Krueppel-like factor 5 (KLF5). Conversely, K6 diminished the protein expression of WW domain-containing protein 1 (WWP1) while activating phosphatase and tensin homolog (PTEN) through c-Myc degradation. This dual action further demonstrated the potential of K6 as a promising therapeutic compound for TP53-mutated CRC.
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Affiliation(s)
- Wei Li
- Yunnan Key Laboratory of Animal Models and Human Disease MechanismsKunming Institute of ZoologyChinese Academy of SciencesKunmingChina
- Kunming College of Life SciencesUniversity of Chinese Academy SciencesKunmingChina
| | - Chuanyu Yang
- Yunnan Key Laboratory of Animal Models and Human Disease MechanismsKunming Institute of ZoologyChinese Academy of SciencesKunmingChina
| | - Zhuo Cheng
- Yunnan Key Laboratory of Animal Models and Human Disease MechanismsKunming Institute of ZoologyChinese Academy of SciencesKunmingChina
- Kunming College of Life SciencesUniversity of Chinese Academy SciencesKunmingChina
| | - Yuanyuan Wu
- School of Chemical Science and TechnologyYunnan UniversityKunmingChina
| | - Sihan Zhou
- School of Chemical Science and TechnologyYunnan UniversityKunmingChina
| | - Xiaowei Qi
- Department of Breast and Thyroid SurgerySouthwest HospitalThe First Affiliated Hospital of the Army Military Medical UniversityChongqingChina
| | - Yi Zhang
- Department of Breast and Thyroid SurgerySouthwest HospitalThe First Affiliated Hospital of the Army Military Medical UniversityChongqingChina
| | - Jinhui Hu
- The First Hospital of Hunan University of Chinese MedicineChangshaChina
| | - Mingjin Xie
- School of Chemical Science and TechnologyYunnan UniversityKunmingChina
| | - Ceshi Chen
- Yunnan Key Laboratory of Animal Models and Human Disease MechanismsKunming Institute of ZoologyChinese Academy of SciencesKunmingChina
- Academy of Biomedical EngineeringKunming Medical UniversityKunmingChina
- The Third Affiliated HospitalKunming Medical UniversityKunmingChina
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Salas-Escabillas DJ, Hoffman MT, Moore JS, Brender SM, Wen HJ, Benitz S, Davis ET, Long D, Wombwell AM, Steele NG, Sears RC, Matsumoto I, DelGiorno KE, Crawford HC. Tuft cells transdifferentiate to neural-like progenitor cells in the progression of pancreatic cancer. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2024:2024.02.12.579982. [PMID: 38405804 PMCID: PMC10888969 DOI: 10.1101/2024.02.12.579982] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/27/2024]
Abstract
Pancreatic ductal adenocarcinoma (PDA) is partly initiated through the transdifferentiation of acinar cells to metaplastic ducts that act as precursors of neoplasia and cancer. Tuft cells are solitary chemosensory cells not found in the normal pancreas but arise in metaplasia and neoplasia, diminishing as neoplastic lesions progress to carcinoma. Metaplastic tuft cells (mTCs) function to suppress tumor progression through communication with the tumor microenvironment, but their fate during progression is unknown. To determine the fate of mTCs during PDA progression, we have created a lineage tracing model that uses a tamoxifen-inducible tuft-cell specific Pou2f3CreERT/+ driver to induce transgene expression, including the lineage tracer tdTomato or the oncogene Myc. mTC lineage trace models of pancreatic neoplasia and carcinoma were used to follow mTC fate. We found that mTCs, in the carcinoma model, transdifferentiate into neural-like progenitor cells (NRPs), a cell type associated with poor survival in PDA patients. Using conditional knock-out and overexpression systems, we found that Myc activity in mTCs is necessary and sufficient to induce this Tuft-to-Neuroendocrine-Transition (TNT).
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Affiliation(s)
- Daniel J. Salas-Escabillas
- Cancer Biology, University of Michigan, Ann Arbor, MI
- Department of Surgery, Henry Ford Health, Detroit, MI
| | - Megan T. Hoffman
- Department of Immunology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA
| | | | | | - Hui-Ju Wen
- Department of Surgery, Henry Ford Health, Detroit, MI
| | - Simone Benitz
- Department of Surgery, Henry Ford Health, Detroit, MI
| | | | - Dan Long
- Department of Surgery, Henry Ford Health, Detroit, MI
| | | | | | - Rosalie C. Sears
- Department of Molecular and Medical Genetics, Oregon Health & Science University, Portland, OR
| | | | - Kathleen E. DelGiorno
- Department of Cell and Developmental Biology, Vanderbilt University School of Medicine, Nashville, TN
| | - Howard C. Crawford
- Department of Surgery, Henry Ford Health, Detroit, MI
- Cancer Biology Program, Wayne State University, Detroit, MI
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Romeo MA, Gilardini Montani MS, Arena A, Benedetti R, D’Orazi G, Cirone M. c-Myc Sustains Pancreatic Cancer Cell Survival and mutp53 Stability through the Mevalonate Pathway. Biomedicines 2022; 10:biomedicines10102489. [PMID: 36289751 PMCID: PMC9599358 DOI: 10.3390/biomedicines10102489] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/12/2022] [Revised: 09/27/2022] [Accepted: 10/02/2022] [Indexed: 11/16/2022] Open
Abstract
It has been shown that wild-type (wt)p53 inhibits oncogene c-Myc while mutant (mut)p53 may transactivate it, with an opposite behavior that frequently occurs in the crosstalk of wt or mutp53 with molecules/pathways promoting carcinogenesis. Even if it has been reported that mutp53 sustains c-Myc, whether c-Myc could in turn influence mutp53 expression remains to be investigated. In this study, we found that pharmacological or genetic inhibition of c-Myc downregulated mutp53, impaired cell survival and increased DNA damage in pancreatic cancer cells. At the molecular level, we observed that c-Myc inhibition reduced the expression of mevalonate kinase (MVK), a molecule belonging to the mevalonate pathway that—according to previous findings—can control mutp53 stability, and thus contributes to cancer cell survival. In conclusion, this study unveils another criminal alliance between oncogenes, such as c-Myc and mutp53, that plays a key role in oncogenesis.
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Affiliation(s)
- Maria Anele Romeo
- Department of Experimental Medicine, Sapienza University of Rome, Viale Regina Elena 324, 00161 Rome, Italy
| | | | - Andrea Arena
- Department of Experimental Medicine, Sapienza University of Rome, Viale Regina Elena 324, 00161 Rome, Italy
| | - Rossella Benedetti
- Department of Experimental Medicine, Sapienza University of Rome, Viale Regina Elena 324, 00161 Rome, Italy
| | - Gabriella D’Orazi
- Department of Research, Advanced Diagnostics, and Technological Innovation, Regina Elena National Cancer Institute, Via Elio Chianesi 53, 00128 Rome, Italy
- Department of Neurosciences, Imaging and Clinical Sciences, University G. D’Annunzio, Via dei Vestini 33, 66100 Chieti, Italy
| | - Mara Cirone
- Department of Experimental Medicine, Sapienza University of Rome, Viale Regina Elena 324, 00161 Rome, Italy
- Correspondence:
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Targeting Post-Translational Regulation of p53 in Colorectal Cancer by Exploiting Vulnerabilities in the p53-MDM2 Axis. Cancers (Basel) 2022; 14:cancers14010219. [PMID: 35008383 PMCID: PMC8750794 DOI: 10.3390/cancers14010219] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/24/2021] [Revised: 12/23/2021] [Accepted: 12/30/2021] [Indexed: 02/05/2023] Open
Abstract
The role played by the key tumor suppressor gene p53 and the implications of p53 mutations for the development and progression of neoplasia continue to expand. This review focuses on colorectal cancer and the regulators of p53 expression and activity identified over the past decade. These newly recognized regulatory mechanisms include (1) direct regulation of mouse double minute 2 homolog (MDM2), an E3 ubiquitin-protein ligase; (2) modulation of the MDM2-p53 interaction; (3) MDM2-independent p53 degradation; and (4) inhibition of p53 nuclear translocation. We positioned these regulatory mechanisms in the context of p53 missense mutations, which not only evade canonical p53 degradation machinery but also exhibit gain-of-function phenotypes that enhance tumor survival and metastasis. Lastly, we discuss current and potential therapeutic strategies directed against p53 mutant-bearing tumors.
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8
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Yan Q. The Yin-Yang Dynamics in Cancer Pharmacogenomics and Personalized Medicine. Methods Mol Biol 2022; 2547:141-163. [PMID: 36068463 DOI: 10.1007/978-1-0716-2573-6_6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 06/15/2023]
Abstract
The enormous heterogeneity of cancer systems has made it very challenging to overcome drug resistance and adverse reactions to achieve personalized therapies. Recent developments in systems biology, especially the perception of cancer as the complex adaptive system (CAS), may help meet the challenges by deciphering the interactions at various levels from the molecular, cellular, tissue-organ, to the whole organism. The ubiquitous Yin-Yang interactions among the coevolving components, including the genes and proteins, decide their spatiotemporal features at various stages from cancer initiation to metastasis. The Yin-Yang imbalances across different systems levels, from genetic mutations to tumor cells adaptation, have been related to the intra- and inter-tumoral heterogeneity in the micro- and macro-environments. At the molecular and cellular levels, dysfunctional Yin-Yang dynamics in the cytokine networks, mitochondrial activities, redox systems, apoptosis, and metabolism can contribute to tumor cell growth and escape of immune surveillance. Up to the organism and system levels, the Yin-Yang imbalances in the cancer microenvironments can lead to different phenotypes from breast cancer to leukemia. These factors may be considered the systems-based biomarkers and treatment targets. The features of adaptation and nonlinearity in Yin-Yang dynamical interactions should be addressed by individualized drug combinations, dosages, intensities, timing, and frequencies at different cancer stages. The comprehensive "Yin-Yang dynamics" framework would enable powerful approaches for personalized and systems medicine strategies.
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Liang Q, Wu J, Zhao X, Shen S, Zhu C, Liu T, Cui X, Chen L, Wei C, Cheng P, Cheng W, Wu A. Establishment of tumor inflammasome clusters with distinct immunogenomic landscape aids immunotherapy. Am J Cancer Res 2021; 11:9884-9903. [PMID: 34815793 PMCID: PMC8581407 DOI: 10.7150/thno.63202] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/26/2021] [Accepted: 10/06/2021] [Indexed: 12/22/2022] Open
Abstract
Inflammasome signaling is a reaction cascade that influences immune response and cell death. Although the inflammasomes participate in tumorigenesis, their role as an oncogenic booster or a tumor suppresser is still controversial. Therefore, it is important to comprehensively investigate the inflammasome signaling status across various cancers to clarify its clinical and therapeutic significance. Methods: A total of 9881 patients across 33 tumor types from The Cancer Genome Atlas database were included in this study. Five gene sets were identified to step-wisely profile inflammasome signaling. Unsupervised clustering was used for sample classification based on gene set enrichment. Machine learning and in vitro and in vivo experiments were used to confirm the implications of inflammasome classification. Results: A hundred and forty-one inflammasome-signaling-related genes were identified to construct five gene sets representing the sensing, activation, and termination steps of the inflammasome signaling. Six inflammasome clusters were robustly established with distinct molecular, biological, clinical, and therapeutic features. Importantly, clusters with inflammasome signaling activation were found to be immunosuppressive and resistant to ICB treatment. Inflammasome inhibition reverted the therapeutic failure of ICB in inflammasome-activated tumors. Moreover, based on the proposed classification and therapeutic implications, an open website was established to provide tumor patients with comprehensive information on inflammasome signaling. Conclusions: Our study conducted a systematical investigation on inflammasome signaling in various tumor types. These findings highlight the importance of inflammasome evaluation in tumor classification and provide a foundation for improving relevant therapeutic regimens.
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Arena A, Gilardini Montani MS, Romeo MA, Benedetti R, Gaeta A, Cirone M. DNA damage triggers an interplay between wtp53 and c-Myc affecting lymphoma cell proliferation and Kaposi sarcoma herpesvirus replication. BIOCHIMICA ET BIOPHYSICA ACTA-MOLECULAR CELL RESEARCH 2021; 1869:119168. [PMID: 34728235 DOI: 10.1016/j.bbamcr.2021.119168] [Citation(s) in RCA: 17] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 07/07/2021] [Revised: 10/26/2021] [Accepted: 10/26/2021] [Indexed: 11/27/2022]
Abstract
The induction of DNA damage together with the interference with DNA repair represents a promising strategy in cancer treatment. Here we show that the PARP-1/2/3 inhibitor AZD2461 in combination with the CHK1 inhibitor UCN-01 altered the DNA damage response and reduced cell proliferation in PEL cells, an aggressive B cell lymphoma highly resistant to chemotherapies. AZD2461/UCN-01 combination activated p53/p21 and downregulated c-Myc in these cells, leading to a reduced expression level of RAD51, molecule involved in DNA repair. The effect of AZD2461/UCN-01 on c-Myc and p53/p21 was inter-dependent and, besides impairing cell proliferation, contributed to the activation of the replicative cycle of KSHV, carried in a latent state in PEL cells. Finally, we found that the pharmacological or genetic inhibition of p21 counteracted the viral lytic cycle activation and further reduced PEL cell proliferation, suggesting that it could induce a double beneficial effect in this setting. This study unveils that, therapeutic approaches, based on the induction of DNA damage and the reduction of DNA repair, could be used to successfully treat this malignant lymphoma.
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Affiliation(s)
- Andrea Arena
- Department of Experimental Medicine, "Sapienza" University of Rome, Laboratory affiliated to Istituto Pasteur Italia-Fondazione Cenci Bolognetti, Rome, Italy
| | - Maria Saveria Gilardini Montani
- Department of Experimental Medicine, "Sapienza" University of Rome, Laboratory affiliated to Istituto Pasteur Italia-Fondazione Cenci Bolognetti, Rome, Italy
| | - Maria Anele Romeo
- Department of Experimental Medicine, "Sapienza" University of Rome, Laboratory affiliated to Istituto Pasteur Italia-Fondazione Cenci Bolognetti, Rome, Italy
| | - Rossella Benedetti
- Department of Experimental Medicine, "Sapienza" University of Rome, Laboratory affiliated to Istituto Pasteur Italia-Fondazione Cenci Bolognetti, Rome, Italy
| | - Aurelia Gaeta
- Department of Molecular Medicine, "Sapienza" University of Rome, Rome, Italy
| | - Mara Cirone
- Department of Experimental Medicine, "Sapienza" University of Rome, Laboratory affiliated to Istituto Pasteur Italia-Fondazione Cenci Bolognetti, Rome, Italy..
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11
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Liu Y, Xin B, Yamamoto M, Goto M, Ooshio T, Kamikokura Y, Tanaka H, Meng L, Okada Y, Mizukami Y, Nishikawa Y. Generation of combined hepatocellular-cholangiocarcinoma through transdifferentiation and dedifferentiation in p53-knockout mice. Cancer Sci 2021; 112:3111-3124. [PMID: 34051011 PMCID: PMC8353893 DOI: 10.1111/cas.14996] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/09/2021] [Revised: 05/11/2021] [Accepted: 05/19/2021] [Indexed: 12/29/2022] Open
Abstract
The two principal histological types of primary liver cancers, hepatocellular carcinoma (HCC) and cholangiocarcinoma, can coexist within a tumor, comprising combined hepatocellular‐cholangiocarcinoma (cHCC‐CCA). Although the possible involvement of liver stem/progenitor cells has been proposed for the pathogenesis of cHCC‐CCA, the cells might originate from transformed hepatocytes that undergo ductular transdifferentiation or dedifferentiation. We previously demonstrated that concomitant introduction of mutant HRASV12 (HRAS) and Myc into mouse hepatocytes induced dedifferentiated tumors that expressed fetal/neonatal liver genes and proteins. Here, we examine whether the phenotype of HRAS‐ or HRAS/Myc‐induced tumors might be affected by the disruption of the Trp53 gene, which has been shown to induce biliary differentiation in mouse liver tumors. Hepatocyte‐derived liver tumors were induced in heterozygous and homozygous p53‐knockout (KO) mice by hydrodynamic tail vein injection of HRAS‐ or Myc‐containing transposon cassette plasmids, which were modified by deleting loxP sites, with a transposase‐expressing plasmid. The HRAS‐induced and HRAS/Myc‐induced tumors in the wild‐type mice demonstrated histological features of HCC, whereas the phenotype of the tumors generated in the p53‐KO mice was consistent with cHCC‐CCA. The expression of fetal/neonatal liver proteins, including delta‐like 1, was detected in the HRAS/Myc‐induced but not in the HRAS‐induced cHCC‐CCA tissues. The dedifferentiation in the HRAS/Myc‐induced tumors was more marked in the homozygous p53‐KO mice than in the heterozygous p53‐KO mice and was associated with activation of Myc and YAP and suppression of ERK phosphorylation. Our results suggest that the loss of p53 promotes ductular differentiation of hepatocyte‐derived tumor cells through either transdifferentiation or Myc‐mediated dedifferentiation.
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Affiliation(s)
- Yang Liu
- Department of Pathology, Division of Tumor Pathology, Asahikawa Medical University, Asahikawa, Japan.,Department of Pathology, the First Affiliated Hospital and College of Basic Medical Sciences of China Medical University, Shenyang, China
| | - Bing Xin
- Department of Pathology, Division of Tumor Pathology, Asahikawa Medical University, Asahikawa, Japan
| | - Masahiro Yamamoto
- Department of Pathology, Division of Tumor Pathology, Asahikawa Medical University, Asahikawa, Japan
| | - Masanori Goto
- Department of Pathology, Division of Tumor Pathology, Asahikawa Medical University, Asahikawa, Japan
| | - Takako Ooshio
- Department of Pathology, Division of Tumor Pathology, Asahikawa Medical University, Asahikawa, Japan
| | - Yuki Kamikokura
- Department of Pathology, Division of Tumor Pathology, Asahikawa Medical University, Asahikawa, Japan
| | - Hiroki Tanaka
- Department of Pathology, Division of Tumor Pathology, Asahikawa Medical University, Asahikawa, Japan
| | - Lingtong Meng
- Department of Pathology, Division of Tumor Pathology, Asahikawa Medical University, Asahikawa, Japan
| | - Yoko Okada
- Department of Pathology, Division of Tumor Pathology, Asahikawa Medical University, Asahikawa, Japan
| | - Yusuke Mizukami
- Department of Medicine, Cancer Genomics and Precision Medicine, Asahikawa Medical University, Asahikawa, Japan
| | - Yuji Nishikawa
- Department of Pathology, Division of Tumor Pathology, Asahikawa Medical University, Asahikawa, Japan
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12
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Zhong M, Zhou L, Zou J, He Y, Fang Z, Xiang X. Cullin-4B promotes cell proliferation and invasion through inactivation of p53 signaling pathway in colorectal cancer. Pathol Res Pract 2021; 224:153520. [PMID: 34153655 DOI: 10.1016/j.prp.2021.153520] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/18/2020] [Revised: 06/06/2021] [Accepted: 06/06/2021] [Indexed: 12/24/2022]
Abstract
Cullin 4B (CUL4B) is a member of the Cullin RING E3 ligase family, which is found to be overexpressed in multiple cancers, thus facilitating tumorigenesis and progression. However, the correlation between CUL4B and p53 in colorectal cancer cells (CRC) remains to be further elucidated. In this study, we newly identified that CUL4B functions as a negative regulator of p53, thereby facilitating CRC tumorigenesis and progression. Our data has demonstrated that CUL4B was frequently overexpressed in CRC tissues, and its upregulation was closely correlated with disease progression and poor prognosis. Moreover, CUL4B knockdown suppressed cell proliferation, invasion and epithelial-mesenchymal transition (EMT) of CRC cells. Mechanistically, CUL4B depletion increased the expression of p53 protein and its downstream targets p21, PUMA and MDM2. Furthermore, CUL4B depletion prolonged the half-life of p53 protein, and CUL4B is a binding partner of MDM2. In conclusion, our study shed new lights on the complex regulatory network between CUL4B and p53, and clarifies this CUL4B-p53 axis contributes greatly to CRC tumorigenesis and progression.
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Affiliation(s)
- Min Zhong
- Department of Oncology, the First Affiliated Hospital of Nanchang University, Nanchang, Jiangxi Province, 330006, China
| | - Ling Zhou
- Department of Oncology, the First Affiliated Hospital of Nanchang University, Nanchang, Jiangxi Province, 330006, China
| | - Jianping Zou
- Department of Oncology, the First Affiliated Hospital of Nanchang University, Nanchang, Jiangxi Province, 330006, China
| | - Yan He
- Department of Oncology, the First Affiliated Hospital of Nanchang University, Nanchang, Jiangxi Province, 330006, China
| | - Ziling Fang
- Department of Oncology, the First Affiliated Hospital of Nanchang University, Nanchang, Jiangxi Province, 330006, China.
| | - Xiaojun Xiang
- Department of Oncology, the First Affiliated Hospital of Nanchang University, Nanchang, Jiangxi Province, 330006, China.
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13
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Lou Z, Lin W, Zhao H, Jiao X, Wang C, Zhao H, Liu L, Liu Y, Xie Q, Huang X, Huang H, Zhao L. Alkaline phosphatase downregulation promotes lung adenocarcinoma metastasis via the c-Myc/RhoA axis. Cancer Cell Int 2021; 21:217. [PMID: 33858415 PMCID: PMC8050923 DOI: 10.1186/s12935-021-01919-7] [Citation(s) in RCA: 17] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/25/2020] [Accepted: 04/07/2021] [Indexed: 12/14/2022] Open
Abstract
BACKGROUND Lung adenocarcinoma (LUAD) metastasis significantly reduces patient survival; hence inhibiting the metastatic ability of lung cancer cells will greatly prolong patient survival. Alkaline phosphatase (ALPL), a homodimeric cell surface phosphohydrolase, is reported to play a controversial role in prostate cancer and ovarian cancer cell migration; however, the function of ALPL in LUAD and the related mechanisms remain unclear. METHODS TCGA database was used to analysis the expression of ALPL, and further verification was performed in a cohort of 36 LUAD samples by qPCR and western blot. Soft-agar assay, transwell assay and lung metastasis assay were employed to detect the function of ALPL in LUAD progression. The qPCR, luciferase promoter reporter assay and western blot were used to clarify the molecular mechanisms of ALPL in promoting metastasis in LUAD. RESULTS ALPL was downregulated in LUAD, and the disease-free survival rate of patients with low ALPL was significantly reduced. Further studies showed that overexpression of ALPL in LUAD cell lines did not significantly affect cell proliferation, but it did significantly attenuate lung metastasis in a mouse model. ALPL downregulation in LUAD led to a decrease in the amount of phosphorylated (p)-ERK. Because p-ERK promotes the classical c-Myc degradation pathway, the decrease in p-ERK led to the accumulation of c-Myc and therefore to an increase in RhoA transcription, which enhanced LUAD cell metastasis. CONCLUSION ALPL specially inhibits the metastasis of LUAD cells by affecting the p-ERK/c-Myc/RhoA axis, providing a theoretical basis for the targeted therapy of clinical LUAD.
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Affiliation(s)
- Zhefeng Lou
- Zhejiang Provincial Key Laboratory of Medical Genetics, Key Laboratory of Laboratory Medicine, Ministry of Education, School of Laboratory Medicine and Life Sciences, Wenzhou Medical University, Wenzhou, 325035, Zhejiang, China
| | - Weiwei Lin
- Zhejiang Provincial Key Laboratory of Medical Genetics, Key Laboratory of Laboratory Medicine, Ministry of Education, School of Laboratory Medicine and Life Sciences, Wenzhou Medical University, Wenzhou, 325035, Zhejiang, China
| | - Huirong Zhao
- Zhejiang Provincial Key Laboratory of Medical Genetics, Key Laboratory of Laboratory Medicine, Ministry of Education, School of Laboratory Medicine and Life Sciences, Wenzhou Medical University, Wenzhou, 325035, Zhejiang, China
| | - Xueli Jiao
- Zhejiang Provincial Key Laboratory of Medical Genetics, Key Laboratory of Laboratory Medicine, Ministry of Education, School of Laboratory Medicine and Life Sciences, Wenzhou Medical University, Wenzhou, 325035, Zhejiang, China
| | - Cong Wang
- Zhejiang Provincial Key Laboratory of Medical Genetics, Key Laboratory of Laboratory Medicine, Ministry of Education, School of Laboratory Medicine and Life Sciences, Wenzhou Medical University, Wenzhou, 325035, Zhejiang, China
| | - He Zhao
- Zhejiang Provincial Key Laboratory of Medical Genetics, Key Laboratory of Laboratory Medicine, Ministry of Education, School of Laboratory Medicine and Life Sciences, Wenzhou Medical University, Wenzhou, 325035, Zhejiang, China
| | - Lu Liu
- Zhejiang Provincial Key Laboratory of Medical Genetics, Key Laboratory of Laboratory Medicine, Ministry of Education, School of Laboratory Medicine and Life Sciences, Wenzhou Medical University, Wenzhou, 325035, Zhejiang, China
| | - Yu Liu
- The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, 325035, Zhejiang, China
| | - Qipeng Xie
- Zhejiang Provincial Key Laboratory of Medical Genetics, Key Laboratory of Laboratory Medicine, Ministry of Education, School of Laboratory Medicine and Life Sciences, Wenzhou Medical University, Wenzhou, 325035, Zhejiang, China
| | - Xing Huang
- Zhejiang Provincial Key Laboratory of Pancreatic Disease, School of Medicine, the First Affiliated Hospital, Zhejiang University, Hangzhou, 310003, Zhejiang, China.
| | - Haishan Huang
- Zhejiang Provincial Key Laboratory of Medical Genetics, Key Laboratory of Laboratory Medicine, Ministry of Education, School of Laboratory Medicine and Life Sciences, Wenzhou Medical University, Wenzhou, 325035, Zhejiang, China.
| | - Lingling Zhao
- Zhejiang Provincial Key Laboratory of Medical Genetics, Key Laboratory of Laboratory Medicine, Ministry of Education, School of Laboratory Medicine and Life Sciences, Wenzhou Medical University, Wenzhou, 325035, Zhejiang, China.
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14
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Gene Transactivation and Transrepression in MYC-Driven Cancers. Int J Mol Sci 2021; 22:ijms22073458. [PMID: 33801599 PMCID: PMC8037706 DOI: 10.3390/ijms22073458] [Citation(s) in RCA: 18] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/22/2021] [Revised: 03/24/2021] [Accepted: 03/25/2021] [Indexed: 12/11/2022] Open
Abstract
MYC is a proto-oncogene regulating a large number of genes involved in a plethora of cellular functions. Its deregulation results in activation of MYC gene expression and/or an increase in MYC protein stability. MYC overexpression is a hallmark of malignant growth, inducing self-renewal of stem cells and blocking senescence and cell differentiation. This review summarizes the latest advances in our understanding of MYC-mediated molecular mechanisms responsible for its oncogenic activity. Several recent findings indicate that MYC is a regulator of cancer genome and epigenome: MYC modulates expression of target genes in a site-specific manner, by recruiting chromatin remodeling co-factors at promoter regions, and at genome-wide level, by regulating the expression of several epigenetic modifiers that alter the entire chromatin structure. We also discuss novel emerging therapeutic strategies based on both direct modulation of MYC and its epigenetic cofactors.
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15
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Feng YC, Liu XY, Teng L, Ji Q, Wu Y, Li JM, Gao W, Zhang YY, La T, Tabatabaee H, Yan XG, Jamaluddin MFB, Zhang D, Guo ST, Scott RJ, Liu T, Thorne RF, Zhang XD, Jin L. c-Myc inactivation of p53 through the pan-cancer lncRNA MILIP drives cancer pathogenesis. Nat Commun 2020; 11:4980. [PMID: 33020477 PMCID: PMC7536215 DOI: 10.1038/s41467-020-18735-8] [Citation(s) in RCA: 82] [Impact Index Per Article: 16.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/05/2019] [Accepted: 09/09/2020] [Indexed: 12/11/2022] Open
Abstract
The functions of the proto-oncoprotein c-Myc and the tumor suppressor p53 in controlling cell survival and proliferation are inextricably linked as “Yin and Yang” partners in normal cells to maintain tissue homeostasis: c-Myc induces the expression of ARF tumor suppressor (p14ARF in human and p19ARF in mouse) that binds to and inhibits mouse double minute 2 homolog (MDM2) leading to p53 activation, whereas p53 suppresses c-Myc through a combination of mechanisms involving transcriptional inactivation and microRNA-mediated repression. Nonetheless, the regulatory interactions between c-Myc and p53 are not retained by cancer cells as is evident from the often-imbalanced expression of c-Myc over wildtype p53. Although p53 repression in cancer cells is frequently associated with the loss of ARF, we disclose here an alternate mechanism whereby c-Myc inactivates p53 through the actions of the c-Myc-Inducible Long noncoding RNA Inactivating P53 (MILIP). MILIP functions to promote p53 polyubiquitination and turnover by reducing p53 SUMOylation through suppressing tripartite-motif family-like 2 (TRIML2). MILIP upregulation is observed amongst diverse cancer types and is shown to support cell survival, division and tumourigenicity. Thus our results uncover an inhibitory axis targeting p53 through a pan-cancer expressed RNA accomplice that links c-Myc to suppression of p53. c-Myc and p53 operate in a negative feedback manner to maintain cellular homeostasis. Here, the authors report a long noncoding RNA, MILIP as a downstream target of c-Myc and that MILIP represses p53 to support tumorigenicity.
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Affiliation(s)
- Yu Chen Feng
- School of Biomedical Sciences and Pharmacy, The University of Newcastle, Newcastle, 2308, NSW, Australia
| | - Xiao Ying Liu
- Translational Research Institute, Henan Provincial People's Hospital and People's Hospital of Zhengzhou University, Academy of Medical Science, Zhengzhou University, Zhengzhou, 450053, Henan, China
| | - Liu Teng
- Translational Research Institute, Henan Provincial People's Hospital and People's Hospital of Zhengzhou University, Academy of Medical Science, Zhengzhou University, Zhengzhou, 450053, Henan, China
| | - Qiang Ji
- Translational Research Institute, Henan Provincial People's Hospital and People's Hospital of Zhengzhou University, Academy of Medical Science, Zhengzhou University, Zhengzhou, 450053, Henan, China
| | - Yongyan Wu
- Department of Otolaryngology, Shanxi Key Laboratory of Otorhinolaryngology Head and Neck Cancer, the first affiliated hospital, Shanxi Medical University, Taiyuan, 030001, Shanxi, China
| | - Jin Ming Li
- Translational Research Institute, Henan Provincial People's Hospital and People's Hospital of Zhengzhou University, Academy of Medical Science, Zhengzhou University, Zhengzhou, 450053, Henan, China
| | - Wei Gao
- Department of Otolaryngology, Shanxi Key Laboratory of Otorhinolaryngology Head and Neck Cancer, the first affiliated hospital, Shanxi Medical University, Taiyuan, 030001, Shanxi, China
| | - Yuan Yuan Zhang
- School of Biomedical Sciences and Pharmacy, The University of Newcastle, Newcastle, 2308, NSW, Australia
| | - Ting La
- School of Biomedical Sciences and Pharmacy, The University of Newcastle, Newcastle, 2308, NSW, Australia
| | - Hessam Tabatabaee
- School of Biomedical Sciences and Pharmacy, The University of Newcastle, Newcastle, 2308, NSW, Australia
| | - Xu Guang Yan
- School of Biomedical Sciences and Pharmacy, The University of Newcastle, Newcastle, 2308, NSW, Australia
| | - M Fairuz B Jamaluddin
- School of Biomedical Sciences and Pharmacy, The University of Newcastle, Newcastle, 2308, NSW, Australia
| | - Didi Zhang
- Department of Orthopaedics, John Hunter Hospital, Hunter New England Health, Newcastle, 2305, NSW, Australia
| | - Su Tang Guo
- Department of Molecular Biology, Shanxi Cancer Hospital and Institute, Taiyuan, 030013, Shanxi, China
| | - Rodney J Scott
- School of Biomedical Sciences and Pharmacy, The University of Newcastle, Newcastle, 2308, NSW, Australia
| | - Tao Liu
- Children's Cancer Institute Australia for Medical Research, University of New South Wales, Sydney, 2750, NSW, Australia
| | - Rick F Thorne
- School of Biomedical Sciences and Pharmacy, The University of Newcastle, Newcastle, 2308, NSW, Australia.,Translational Research Institute, Henan Provincial People's Hospital and People's Hospital of Zhengzhou University, Academy of Medical Science, Zhengzhou University, Zhengzhou, 450053, Henan, China
| | - Xu Dong Zhang
- School of Biomedical Sciences and Pharmacy, The University of Newcastle, Newcastle, 2308, NSW, Australia. .,Translational Research Institute, Henan Provincial People's Hospital and People's Hospital of Zhengzhou University, Academy of Medical Science, Zhengzhou University, Zhengzhou, 450053, Henan, China.
| | - Lei Jin
- Translational Research Institute, Henan Provincial People's Hospital and People's Hospital of Zhengzhou University, Academy of Medical Science, Zhengzhou University, Zhengzhou, 450053, Henan, China. .,School of Medicine and Public Health, The University of Newcastle, Newcastle, 2308, NSW, Australia.
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16
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Hao Q, Chen Y, Zhou X. The Janus Face of p53-Targeting Ubiquitin Ligases. Cells 2020; 9:cells9071656. [PMID: 32660118 PMCID: PMC7407405 DOI: 10.3390/cells9071656] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/16/2020] [Revised: 07/03/2020] [Accepted: 07/06/2020] [Indexed: 12/11/2022] Open
Abstract
The tumor suppressor p53 prevents tumorigenesis and cancer progression by maintaining genomic stability and inducing cell growth arrest and apoptosis. Because of the extremely detrimental nature of wild-type p53, cancer cells usually mutate the TP53 gene in favor of their survival and propagation. Some of the mutant p53 proteins not only lose the wild-type activity, but also acquire oncogenic function, namely “gain-of-function”, to promote cancer development. Growing evidence has revealed that various E3 ubiquitin ligases are able to target both wild-type and mutant p53 for degradation or inactivation, and thus play divergent roles leading to cancer cell survival or death in the context of different p53 status. In this essay, we reviewed the recent progress in our understanding of the p53-targeting E3 ubiquitin ligases, and discussed the potential clinical implications of these E3 ubiquitin ligases in cancer therapy.
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Affiliation(s)
- Qian Hao
- Fudan University Shanghai Cancer Center and Institutes of Biomedical Sciences, Fudan University, Shanghai 200032, China;
| | - Yajie Chen
- Department of Radiation Oncology, Fudan University Shanghai Cancer Center, Fudan University, Shanghai 200032, China;
| | - Xiang Zhou
- Fudan University Shanghai Cancer Center and Institutes of Biomedical Sciences, Fudan University, Shanghai 200032, China;
- Key Laboratory of Breast Cancer in Shanghai, Fudan University Shanghai Cancer Center, Fudan University, Shanghai 200032, China
- Shanghai Key Laboratory of Medical Epigenetics, International Co-laboratory of Medical Epigenetics and Metabolism, Ministry of Science and Technology, Institutes of Biomedical Sciences, Fudan University, Shanghai 200032, China
- Correspondence: ; Tel.: +86-21-54237325
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17
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Zhu L, Huang S, Li J, Chen J, Yao Y, Li L, Guo H, Xiang X, Deng J, Xiong J. Sophoridine inhibits lung cancer cell growth and enhances cisplatin sensitivity through activation of the p53 and Hippo signaling pathways. Gene 2020; 742:144556. [PMID: 32165304 DOI: 10.1016/j.gene.2020.144556] [Citation(s) in RCA: 27] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/05/2019] [Accepted: 03/08/2020] [Indexed: 02/07/2023]
Abstract
BACKGROUND Sophoridine, a quinolizidine alkaloid extracted from the Chinese herb Sophora alopecuroides L., has been reported to exert antitumor effects against multiple human cancers. However, few studies have evaluated its tumor-suppressing effects and associated mechanism with respect to lung cancer, in addition to its potential to be used for clinical lung cancer treatment. METHODS Different types of lung cancer cells were used to investigate the antitumor effects of sophoridine using cell viability, colony formation, and cell invasion, and migration assays. To determine the signaling pathways involved, western blot analysis, quantitative real-time polymerase chain reaction, an in vivo ubiquitination assay, and immunohistochemistry were used in cellular assays and with a subcutaneous xenograft model in BALB/c mice. RESULTS Sophoridine significantly suppressed the proliferation of and colony formation by lung cancer cells in vitro. Transwell assays demonstrated that sophoridine also inhibited invasion and migration in lung cancer cells. In addition, sophoridine enhanced the effects of cisplatin on lung cancer cells. A mechanistic study revealed that sophoridine significantly activated the Hippo and p53 signaling pathways, and mouse xenograft experiments further confirmed in vitro findings in lung cancer cells. CONCLUSIONS Taken together, these results suggest that sophoridine can inhibit lung cancer progression and enhance the effects of the anticancer drug cisplatin against lung cancer cells. The mechanism of action of sophoridine might involve the Hippo and p53 signaling pathways.
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Affiliation(s)
- Lingling Zhu
- Department of Oncology, The First Affiliated Hospital of Nanchang University, Nanchang, Jiangxi Province 330006, China; Lung Cancer Center, West China Hospital of Sichuan University, Chengdu, China
| | - Shanshan Huang
- Department of Oncology, The First Affiliated Hospital of Nanchang University, Nanchang, Jiangxi Province 330006, China
| | - Junhe Li
- Department of Oncology, The First Affiliated Hospital of Nanchang University, Nanchang, Jiangxi Province 330006, China
| | - Jun Chen
- Department of Oncology, The First Affiliated Hospital of Nanchang University, Nanchang, Jiangxi Province 330006, China
| | - Yangyang Yao
- Department of Oncology, The First Affiliated Hospital of Nanchang University, Nanchang, Jiangxi Province 330006, China
| | - Li Li
- Department of Oncology, The First Affiliated Hospital of Nanchang University, Nanchang, Jiangxi Province 330006, China
| | - Hui Guo
- Department of Oncology, The First Affiliated Hospital of Nanchang University, Nanchang, Jiangxi Province 330006, China
| | - Xiaojun Xiang
- Department of Oncology, The First Affiliated Hospital of Nanchang University, Nanchang, Jiangxi Province 330006, China.
| | - Jun Deng
- Department of Oncology, The First Affiliated Hospital of Nanchang University, Nanchang, Jiangxi Province 330006, China.
| | - Jianping Xiong
- Department of Oncology, The First Affiliated Hospital of Nanchang University, Nanchang, Jiangxi Province 330006, China.
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18
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Wu P, Ding B, Ye L, Huang Y, Ji J, Fan Y, Xu L. Zhibaidihuang Decoction Ameliorates Cell Oxidative Stress by Regulating the Keap1-Nrf2-ARE Signalling Pathway. EVIDENCE-BASED COMPLEMENTARY AND ALTERNATIVE MEDICINE : ECAM 2020; 2020:9294605. [PMID: 32104200 PMCID: PMC7037871 DOI: 10.1155/2020/9294605] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 10/13/2019] [Revised: 12/23/2019] [Accepted: 01/07/2020] [Indexed: 01/09/2023]
Abstract
Zhibaidihuang decoction (ZBDHD) is a Chinese herbal formula, which is used in Chinese traditional medicine to treat symptoms of Yinxuhuowang (Yin deficiency and high fire) syndrome. This study elucidates the mechanism of ZBDHD on oral ulcers, one Yinxuhuowang syndrome. Simultaneously, some ingredients in ZBDHD were found and identified by ultraperformance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS). A Ganjiangfuzirougui decoction- (GJD-) induced Yinxuhuowang syndrome SD rat model was used to demonstrate the efficiency of ZBDHD treatment. The oral mucosa of rat in the GJD group, stained with hematoxylin and eosin (H&E), showed epidermal shedding and inflammatory cell infiltration. And an alleviation efficiency of ZBDHD in GJD-induced pathological changes in the oral mucosa could be obtained. ZBDHD treatment restored the GJD-induced imbalance of metabolites, which were choline, glycocholic acid, and palmitoyl-L-carnitine (PALC). GJD stimulated the expression of NF-κB. And the overexpressed of NF-κB in mucosa of rat in the GJD group could be inhibited by ZBDHD treatment. Simultaneously, the optimal efficiency of ZBDHD treatment on the cellular ATP content, oxygen consumption rate (OCR), and superoxide dismutase (SOD) concentration was evaluated, in vitro assay. Compared to the control cells, the ATP content, OCR, and SOD activity in the ZBDHD-treated cells were significantly higher. For the mechanisms study, seven cytokines were screened with a Dual-Luciferase Reporter gene assay. In the ARE assay, the luciferase signal was stimulated significantly by ZBDHD. In cells, the transcription of nrf2, maf, and keap1, which were related to the ARE pathway, was elevated by ZBDHD treatment. Our study demonstrated that high-dose GJD could lead to Yinxuhuowang syndrome, such as oral ulcers, and the imbalance in serum metabolites. And ZBDHD can improve oral cell inflammation and the imbalance of metabolism by inhibiting NF-κB and enhancing the activity of the ARE signalling pathway to ameliorate oxidative stress in the cell. This study provides a theoretical basis for the clinical application of ZBDHD.
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Affiliation(s)
- Pingping Wu
- College of Basic Medicine, Zhejiang Chinese Medical University, Hangzhou, Zhejiang, China
| | - Bin Ding
- College of Life Science, Zhejiang Chinese Medical University, Hangzhou, Zhejiang, China
| | - Li Ye
- College of Basic Medicine, Zhejiang Chinese Medical University, Hangzhou, Zhejiang, China
| | - Yanfen Huang
- College of Life Science, Zhejiang Chinese Medical University, Hangzhou, Zhejiang, China
| | - Jinjun Ji
- College of Basic Medicine, Zhejiang Chinese Medical University, Hangzhou, Zhejiang, China
| | - Yongsheng Fan
- First Clinical Medical College, Zhejiang Chinese Medical University, Hangzhou, Zhejiang, China
| | - Li Xu
- College of Basic Medicine, Zhejiang Chinese Medical University, Hangzhou, Zhejiang, China
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19
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c-Myc promotes tubular cell apoptosis in ischemia-reperfusion-induced renal injury by negatively regulating c-FLIP and enhancing FasL/Fas-mediated apoptosis pathway. Acta Pharmacol Sin 2019; 40:1058-1066. [PMID: 30593588 DOI: 10.1038/s41401-018-0201-9] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/03/2018] [Accepted: 11/29/2018] [Indexed: 12/16/2022]
Abstract
c-Myc plays an important role in cell proliferation, differentiation, and cell apoptosis. FasL/Fas pathway is a key regulator of cell apoptosis. This study was aimed to investigate the effects of c-Myc on the FasL/Fas pathway in ischemia-reperfusion (I/R)-induced renal injury. Rats were objected to bilateral renal ischemia for 60 min and reperfused for 24 or 48 h. NRK-52E cells were treated with hypoxia-reoxygenation (H/R) or FasL. Immunohistochemistry was used to identify the distribution of c-Myc. Cell apoptosis was assessed by TUNEL staining. Ad-c-Myc and recombinant pcDAN 3.0 were used to overexpress c-Myc and c-FLIP, respectively. ChIP assay and luciferase assay were used to detect the binding of c-Myc to c-FLIP promoter. In I/R rats, c-Myc was increased significantly and mainly located in renal tubular epithelial cells; meanwhile, c-FLIP was decreased, cleaved caspase-8, cleaved caspase-3 and TUNEL-positive staining cells were increased. Treatment of I/R rats with c-Myc inhibitor 10058-F4 significantly attenuated the decrease in c-FLIP, the increase in cleaved caspase-8, cleaved caspase-3, TUNEL-positive cells, Scr and BUN in I/R rats. In NRK-52E cells, hypoxia and reoxygen induced the increase in c-Myc and decrease in c-FLIP. ChIP and luciferase assay results indicated that c-Myc binds to the promoter region of c-FLIP gene. Overexpression of c-Myc markedly decreased c-FLIP. Overexpression of c-FLIP inhibited the increase in cleaved caspase-8 and caspase-3 induced by FasL. Data indicated that c-Myc is increased in kidneys of I/R rats and negatively regulates the expression of c-FLIP, then enhanced FasL-induced cell apoptosis in I/R stress.
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20
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Molavi G, Samadi N, Hosseingholi EZ. The roles of moonlight ribosomal proteins in the development of human cancers. J Cell Physiol 2018; 234:8327-8341. [PMID: 30417503 DOI: 10.1002/jcp.27722] [Citation(s) in RCA: 25] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/16/2018] [Accepted: 09/23/2018] [Indexed: 12/13/2022]
Abstract
"Moonlighting protein" is a term used to define a single protein with multiple functions and different activities that are not derived from gene fusions, multiple RNA splicing, or the proteolytic activity of promiscuous enzymes. Different proteinous constituents of ribosomes have been shown to have important moonlighting extra-ribosomal functions. In this review, we introduce the impact of key moonlight ribosomal proteins and dependent signal transduction in the initiation and progression of various cancers. As a future perspective, the potential role of these moonlight ribosomal proteins in the diagnosis, prognosis, and development of novel strategies to improve the efficacy of therapies for human cancers has been suggested.
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Affiliation(s)
- Ghader Molavi
- Drug Applied Research Center, Tabriz University of Medical Sciences, Tabriz, Iran.,Department of Molecular Medicine, Faculty of Advanced Medical Sciences, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Nasser Samadi
- Drug Applied Research Center, Tabriz University of Medical Sciences, Tabriz, Iran.,Department of Molecular Medicine, Faculty of Advanced Medical Sciences, Tabriz University of Medical Sciences, Tabriz, Iran.,Department of Biochemistry, Faculty of Medicine, Tabriz University of Medical Sciences, Tabriz, Iran
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21
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p53 and glucose metabolism: an orchestra to be directed in cancer therapy. Pharmacol Res 2018; 131:75-86. [DOI: 10.1016/j.phrs.2018.03.015] [Citation(s) in RCA: 80] [Impact Index Per Article: 11.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/29/2017] [Revised: 02/23/2018] [Accepted: 03/20/2018] [Indexed: 12/14/2022]
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22
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Fang Z, Cao B, Liao JM, Deng J, Plummer KD, Liao P, Liu T, Zhang W, Zhang K, Li L, Margolin D, Zeng SX, Xiong J, Lu H. SPIN1 promotes tumorigenesis by blocking the uL18 (universal large ribosomal subunit protein 18)-MDM2-p53 pathway in human cancer. eLife 2018; 7:31275. [PMID: 29547122 PMCID: PMC5871334 DOI: 10.7554/elife.31275] [Citation(s) in RCA: 42] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/15/2017] [Accepted: 03/13/2018] [Indexed: 12/14/2022] Open
Abstract
Ribosomal proteins (RPs) play important roles in modulating the MDM2-p53 pathway. However, less is known about the upstream regulators of the RPs. Here, we identify SPIN1 (Spindlin 1) as a novel binding partner of human RPL5/uL18 that is important for this pathway. SPIN1 ablation activates p53, suppresses cell growth, reduces clonogenic ability, and induces apoptosis of human cancer cells. Mechanistically, SPIN1 sequesters uL18 in the nucleolus, preventing it from interacting with MDM2, and thereby alleviating uL18-mediated inhibition of MDM2 ubiquitin ligase activity toward p53. SPIN1 deficiency increases ribosome-free uL18 and uL5 (human RPL11), which are required for SPIN1 depletion-induced p53 activation. Analysis of cancer genomic databases suggests that SPIN1 is highly expressed in several human cancers, and its overexpression is positively correlated with poor prognosis in cancer patients. Altogether, our findings reveal that the oncogenic property of SPIN1 may be attributed to its negative regulation of uL18, leading to p53 inactivation.
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Affiliation(s)
- Ziling Fang
- Department of Biochemistry and Molecular Biology, Tulane University School of Medicine, New Orleans, United States
| | - Bo Cao
- Department of Biochemistry and Molecular Biology, Tulane University School of Medicine, New Orleans, United States
| | - Jun-Ming Liao
- Department of Biochemistry and Molecular Biology, Tulane University School of Medicine, New Orleans, United States.,School of Dentistry at Case Western University, Cleveland, United States
| | - Jun Deng
- Department of Biochemistry and Molecular Biology, Tulane University School of Medicine, New Orleans, United States
| | - Kevin D Plummer
- Department of Biochemistry and Molecular Biology, Tulane University School of Medicine, New Orleans, United States
| | - Peng Liao
- Department of Biochemistry and Molecular Biology, Tulane University School of Medicine, New Orleans, United States
| | - Tao Liu
- Department of Biochemistry and Molecular Biology, Tulane University School of Medicine, New Orleans, United States
| | - Wensheng Zhang
- Department of Computer Science, Bioinformatics Facility of Xavier RCMI Center of Cancer Research, Xavier University of Louisiana, New Orleans, United States
| | - Kun Zhang
- Department of Computer Science, Bioinformatics Facility of Xavier RCMI Center of Cancer Research, Xavier University of Louisiana, New Orleans, United States
| | - Li Li
- Laboratory of Translational Cancer Research, Ochsner Clinical Foundation, New Orleans, United States
| | - David Margolin
- Department of Colon and Rectal Surgery, Ochsner Clinical Foundation, New Orleans, United States
| | - Shelya X Zeng
- Department of Biochemistry and Molecular Biology, Tulane University School of Medicine, New Orleans, United States
| | - Jianping Xiong
- Department of Oncology, The First Affiliated Hospital of Nanchang University, Nanchang, China
| | - Hua Lu
- Department of Biochemistry and Molecular Biology, Tulane University School of Medicine, New Orleans, United States
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Wei S. Yin-yang regulating effects of cancer-associated genes, proteins, and cells: An ancient Chinese concept in vogue in modern cancer research. Biosci Trends 2017; 11:612-618. [PMID: 29238002 DOI: 10.5582/bst.2017.01259] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/05/2022]
Abstract
Great achievements have been made in human cancer research, but most of this research is focused on conditions at the microscopic rather than the systemic level. Recent studies have increasingly cited the ancient Chinese theory of yin-yang in an effort to expand beyond the microscopic level. Various cancer-associated genes and proteins such as mitogen-activated protein kinase (MAPK), p38, p53, c-Myc, tumor necrosis factor (TNF)-α, NF-κB, Cyclin D1, and cyclin-dependent kinase (CDK) and cells such as T cells, B cells, macrophages, neutrophils, and fibroblasts have been reported to regulate various types of cancers in a yin-yang manner. These studies have brought the theory of yin-yang into vogue in cancer research worldwide.
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Affiliation(s)
- Shuyong Wei
- College of Animal Science, Southwest University
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24
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Lee HJ, Wolosin JM, Chung SH. Divergent effects of Wnt/β-catenin signaling modifiers on the preservation of human limbal epithelial progenitors according to culture condition. Sci Rep 2017; 7:15241. [PMID: 29127331 PMCID: PMC5681568 DOI: 10.1038/s41598-017-15454-x] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/29/2017] [Accepted: 10/25/2017] [Indexed: 11/10/2022] Open
Abstract
Wnt signaling plays an important role in the regulation of self-renewal in stem cells. Here we investigated the effect of CHIR99021, the primary transducer of the Wnt signaling canonical pathway, and IWP2, a wide action Wnt signal blocker, on the growth and differentiation of the limbal epithelial progenitor cells when these cells are cultured in two different, common culture approaches, outgrowth from limbal biopsy explants and isolated cell seeded in low calcium medium. Consistent with their expected effects, irrespective of the culture system, IWP2 decreased total β-catenin while CHIR99021 increased it in nuclear localization. However, IWP2 increased stem/progenitor cell marker (p63α and ABCG2) content and clonogenic capacity in the explants but had opposite effects on isolated cells. CHIR99021 reduced the growth rate, stem/progenitor cell marker content and clonogenic capacity in the explants but also had the opposite effect on the isolated cells. These results show that the outcome of Wnt/β-catenin signaling modification is dependent on the culture systems. Transplantation of limbal epithelial sheets from explant cultures is one of the standard treatments of limbal stem cell deficiency. Our study shows that Wnt-associated activity has a strong negative impact on stem/progenitor cell preservation in limbal explant cultures.
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Affiliation(s)
- Hyun Jung Lee
- Department of Ophthalmology and Visual Science, Catholic Institute of Visual Science, College of Medicine, The Catholic University of Korea, Seoul St. Mary's Hospital, Seoul, Republic of Korea
| | - J Mario Wolosin
- Department of Ophthalmology, Eye and Vison Research Institute and Black Family Stem Cell Institute, Icahn School of Medicine at Mount Sinai, New York, NY, United States of America.
| | - So-Hyang Chung
- Department of Ophthalmology and Visual Science, Catholic Institute of Visual Science, College of Medicine, The Catholic University of Korea, Seoul St. Mary's Hospital, Seoul, Republic of Korea.
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25
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Bian B, Bigonnet M, Gayet O, Loncle C, Maignan A, Gilabert M, Moutardier V, Garcia S, Turrini O, Delpero JR, Giovannini M, Grandval P, Gasmi M, Ouaissi M, Secq V, Poizat F, Nicolle R, Blum Y, Marisa L, Rubis M, Raoul JL, Bradner JE, Qi J, Lomberk G, Urrutia R, Saul A, Dusetti N, Iovanna J. Gene expression profiling of patient-derived pancreatic cancer xenografts predicts sensitivity to the BET bromodomain inhibitor JQ1: implications for individualized medicine efforts. EMBO Mol Med 2017; 9:482-497. [PMID: 28275007 PMCID: PMC5376755 DOI: 10.15252/emmm.201606975] [Citation(s) in RCA: 58] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/25/2022] Open
Abstract
c-MYC controls more than 15% of genes responsible for proliferation, differentiation, and cellular metabolism in pancreatic as well as other cancers making this transcription factor a prime target for treating patients. The transcriptome of 55 patient-derived xenografts show that 30% of them share an exacerbated expression profile of MYC transcriptional targets (MYC-high). This cohort is characterized by a high level of Ki67 staining, a lower differentiation state, and a shorter survival time compared to the MYC-low subgroup. To define classifier expression signature, we selected a group of 10 MYC target transcripts which expression is increased in the MYC-high group and six transcripts increased in the MYC-low group. We validated the ability of these markers panel to identify MYC-high patient-derived xenografts from both: discovery and validation cohorts as well as primary cell cultures from the same patients. We then showed that cells from MYC-high patients are more sensitive to JQ1 treatment compared to MYC-low cells, in monolayer, 3D cultured spheroids and in vivo xenografted tumors, due to cell cycle arrest followed by apoptosis. Therefore, these results provide new markers and potentially novel therapeutic modalities for distinct subgroups of pancreatic tumors and may find application to the future management of these patients within the setting of individualized medicine clinics.
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Affiliation(s)
- Benjamin Bian
- Centre de Recherche en Cancérologie de Marseille (CRCM), INSERM U1068, CNRS UMR 7258, Parc Scientifique et Technologique de Luminy, Aix-Marseille Université and Institut Paoli-Calmettes, Marseille, France
| | - Martin Bigonnet
- Centre de Recherche en Cancérologie de Marseille (CRCM), INSERM U1068, CNRS UMR 7258, Parc Scientifique et Technologique de Luminy, Aix-Marseille Université and Institut Paoli-Calmettes, Marseille, France
| | - Odile Gayet
- Centre de Recherche en Cancérologie de Marseille (CRCM), INSERM U1068, CNRS UMR 7258, Parc Scientifique et Technologique de Luminy, Aix-Marseille Université and Institut Paoli-Calmettes, Marseille, France
| | - Celine Loncle
- Centre de Recherche en Cancérologie de Marseille (CRCM), INSERM U1068, CNRS UMR 7258, Parc Scientifique et Technologique de Luminy, Aix-Marseille Université and Institut Paoli-Calmettes, Marseille, France
| | - Aurélie Maignan
- Centre de Recherche en Cancérologie de Marseille (CRCM), INSERM U1068, CNRS UMR 7258, Parc Scientifique et Technologique de Luminy, Aix-Marseille Université and Institut Paoli-Calmettes, Marseille, France
| | - Marine Gilabert
- Centre de Recherche en Cancérologie de Marseille (CRCM), INSERM U1068, CNRS UMR 7258, Parc Scientifique et Technologique de Luminy, Aix-Marseille Université and Institut Paoli-Calmettes, Marseille, France
| | - Vincent Moutardier
- Centre de Recherche en Cancérologie de Marseille (CRCM), INSERM U1068, CNRS UMR 7258, Parc Scientifique et Technologique de Luminy, Aix-Marseille Université and Institut Paoli-Calmettes, Marseille, France.,Hôpital Nord, Marseille, France.,CIC1409, AP-HM-Hôpital Nord, Aix-Marseille Université, Marseille, France
| | - Stephane Garcia
- Centre de Recherche en Cancérologie de Marseille (CRCM), INSERM U1068, CNRS UMR 7258, Parc Scientifique et Technologique de Luminy, Aix-Marseille Université and Institut Paoli-Calmettes, Marseille, France.,Hôpital Nord, Marseille, France
| | - Olivier Turrini
- Centre de Recherche en Cancérologie de Marseille (CRCM), INSERM U1068, CNRS UMR 7258, Parc Scientifique et Technologique de Luminy, Aix-Marseille Université and Institut Paoli-Calmettes, Marseille, France.,Institut Paoli-Calmettes, Marseille, France
| | | | | | | | - Mohamed Gasmi
- Hôpital Nord, Marseille, France.,CIC1409, AP-HM-Hôpital Nord, Aix-Marseille Université, Marseille, France
| | | | | | | | - Rémy Nicolle
- Programme Cartes d'Identité des Tumeurs (CIT), Ligue Nationale Contre Le Cancer, Paris, France
| | - Yuna Blum
- Programme Cartes d'Identité des Tumeurs (CIT), Ligue Nationale Contre Le Cancer, Paris, France
| | - Laetitia Marisa
- Programme Cartes d'Identité des Tumeurs (CIT), Ligue Nationale Contre Le Cancer, Paris, France
| | - Marion Rubis
- Centre de Recherche en Cancérologie de Marseille (CRCM), INSERM U1068, CNRS UMR 7258, Parc Scientifique et Technologique de Luminy, Aix-Marseille Université and Institut Paoli-Calmettes, Marseille, France
| | | | - James E Bradner
- Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA
| | - Jun Qi
- Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA
| | - Gwen Lomberk
- Laboratory of Epigenetics and Chromatin Dynamics, Departments of Biochemistry and Molecular Biology and Medicine, Mayo Clinic, Rochester, MN, USA
| | - Raul Urrutia
- Laboratory of Epigenetics and Chromatin Dynamics, Departments of Biochemistry and Molecular Biology and Medicine, Mayo Clinic, Rochester, MN, USA
| | - Andres Saul
- Centre Interdisciplinaire de Nanoscience de Marseille-CNRS UMR 7325, Parc Scientifique et Technologique de Luminy, Aix-Marseille Université, Marseille, France
| | - Nelson Dusetti
- Centre de Recherche en Cancérologie de Marseille (CRCM), INSERM U1068, CNRS UMR 7258, Parc Scientifique et Technologique de Luminy, Aix-Marseille Université and Institut Paoli-Calmettes, Marseille, France
| | - Juan Iovanna
- Centre de Recherche en Cancérologie de Marseille (CRCM), INSERM U1068, CNRS UMR 7258, Parc Scientifique et Technologique de Luminy, Aix-Marseille Université and Institut Paoli-Calmettes, Marseille, France
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26
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Lee JS, Choi HJ, Baek SH. Sumoylation and Its Contribution to Cancer. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2017; 963:283-298. [PMID: 28197919 DOI: 10.1007/978-3-319-50044-7_17] [Citation(s) in RCA: 37] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Subscribe] [Scholar Register] [Indexed: 11/25/2022]
Abstract
Post-translational modifications play an important role in regulating protein activity by altering their functions. Sumoylation is a highly dynamic process which is tightly regulated by a fine balance between conjugating and deconjugating enzyme activities. It affects intracellular localization and their interaction with their binding partners, thereby changing gene expression. Consequently, these changes in turn affect signaling mechanisms that regulate many cellular functions, such as cell growth, proliferation, apoptosis , DNA repair , and cell survival. It is becoming apparent that deregulation in the SUMO pathway contributes to oncogenic transformation by affecting sumoylation/desumoylation of many oncoproteins and tumor suppressors. Loss of balance between sumoylation and desumoylation has been reported in a number of studies in a variety of disease types including cancer. This chapter summarizes the mechanisms and functions of the deregulated SUMO pathway affecting oncogenes and tumor suppressor genes.
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Affiliation(s)
- Jason S Lee
- Department of Biological Sciences, Seoul National University, Seoul, 151-742, South Korea
| | - Hee June Choi
- Department of Biological Sciences, Seoul National University, Seoul, 151-742, South Korea
| | - Sung Hee Baek
- Department of Biological Sciences, Seoul National University, Seoul, 151-742, South Korea.
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27
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Lauinger L, Li J, Shostak A, Cemel IA, Ha N, Zhang Y, Merkl PE, Obermeyer S, Stankovic-Valentin N, Schafmeier T, Wever WJ, Bowers AA, Carter KP, Palmer AE, Tschochner H, Melchior F, Deshaies RJ, Brunner M, Diernfellner A. Thiolutin is a zinc chelator that inhibits the Rpn11 and other JAMM metalloproteases. Nat Chem Biol 2017; 13:709-714. [PMID: 28459440 DOI: 10.1038/nchembio.2370] [Citation(s) in RCA: 96] [Impact Index Per Article: 12.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/30/2016] [Accepted: 03/22/2017] [Indexed: 12/21/2022]
Abstract
Thiolutin is a disulfide-containing antibiotic and anti-angiogenic compound produced by Streptomyces. Its biological targets are not known. We show that reduced thiolutin is a zinc chelator that inhibits the JAB1/MPN/Mov34 (JAMM) domain-containing metalloprotease Rpn11, a deubiquitinating enzyme of the 19S proteasome. Thiolutin also inhibits the JAMM metalloproteases Csn5, the deneddylase of the COP9 signalosome; AMSH, which regulates ubiquitin-dependent sorting of cell-surface receptors; and BRCC36, a K63-specific deubiquitinase of the BRCC36-containing isopeptidase complex and the BRCA1-BRCA2-containing complex. We provide evidence that other dithiolopyrrolones also function as inhibitors of JAMM metalloproteases.
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Affiliation(s)
- Linda Lauinger
- Heidelberg University Biochemistry Center, Heidelberg, Germany
| | - Jing Li
- Division of Biology and Biological Engineering, California Institute of Technology, Pasadena, California, USA
| | - Anton Shostak
- Heidelberg University Biochemistry Center, Heidelberg, Germany
| | | | - Nati Ha
- Heidelberg University Biochemistry Center, Heidelberg, Germany
| | - Yaru Zhang
- Division of Biology and Biological Engineering, California Institute of Technology, Pasadena, California, USA
| | - Philipp E Merkl
- Lehrstuhl Biochemie III, Biochemie Zentrum Regensburg, Universität Regensburg, Regensburg, Germany
| | - Simon Obermeyer
- Lehrstuhl Biochemie III, Biochemie Zentrum Regensburg, Universität Regensburg, Regensburg, Germany
| | - Nicolas Stankovic-Valentin
- Zentrum Molekulare Biologie der Universität Heidelberg, DKFZ-ZMBH Alliance, Heidelberg University, Heidelberg, Germany
| | | | - Walter J Wever
- Division of Chemical Biology and Medicinal Chemistry, Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA
| | - Albert A Bowers
- Division of Chemical Biology and Medicinal Chemistry, Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA
| | - Kyle P Carter
- Department of Chemistry and Biochemistry, BioFrontiers Institute, University of Colorado Boulder, Boulder, Colorado, USA
| | - Amy E Palmer
- Department of Chemistry and Biochemistry, BioFrontiers Institute, University of Colorado Boulder, Boulder, Colorado, USA
| | - Herbert Tschochner
- Lehrstuhl Biochemie III, Biochemie Zentrum Regensburg, Universität Regensburg, Regensburg, Germany
| | - Frauke Melchior
- Zentrum Molekulare Biologie der Universität Heidelberg, DKFZ-ZMBH Alliance, Heidelberg University, Heidelberg, Germany
| | - Raymond J Deshaies
- Division of Biology and Biological Engineering, California Institute of Technology, Pasadena, California, USA.,Howard Hughes Medical Institute, California Institute of Technology, Pasadena, California, USA
| | - Michael Brunner
- Heidelberg University Biochemistry Center, Heidelberg, Germany
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28
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Chao T, Zhou X, Cao B, Liao P, Liu H, Chen Y, Park HW, Zeng SX, Lu H. Pleckstrin homology domain-containing protein PHLDB3 supports cancer growth via a negative feedback loop involving p53. Nat Commun 2016; 7:13755. [PMID: 28008906 PMCID: PMC5196188 DOI: 10.1038/ncomms13755] [Citation(s) in RCA: 29] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/20/2016] [Accepted: 10/31/2016] [Indexed: 12/20/2022] Open
Abstract
The tumour suppressor p53 transactivates the expression of its target genes to exert its functions. Here, we identify a pleckstrin homology domain-containing protein (PHLDB3)-encoding gene as a p53 target. PHLDB3 overexpression increases proliferation and restrains apoptosis of wild-type p53-harboring cancer cells by reducing p53 protein levels. PHLDB3 binds to MDM2 (mouse double minute 2 homolog) and facilitates MDM2-mediated ubiquitination and degradation of p53. Knockdown of PHLDB3 more efficiently inhibits the growth of mouse xenograft tumours derived from human colon cancer HCT116 cells that contain wild type p53 compared with p53-deficient HCT116 cells, and also sensitizes tumour cells to doxorubicin and 5-Fluorouracil. Analysis of cancer genomic databases reveals that PHLDB3 is amplified and/or highly expressed in numerous human cancers. Altogether, these results demonstrate that PHLDB3 promotes tumour growth by inactivating p53 in a negative feedback fashion and suggest PHLDB3 as a potential therapeutic target in various human cancers. p53 is an oncosuppressor regulating several genes at the transcriptional level. Here, the authors identify a negative feedback loop between PHLDB3 and p53; PHLDB3 is a transcriptional target of p53 which facilitates MDM2-mediated p53 ubiquitination and degradation, impacting on tumorigenesis.
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Affiliation(s)
- Tengfei Chao
- Department of Biochemistry &Molecular Biology, Tulane University School of Medicine, New Orleans, Louisiana 70112, USA.,Tulane Cancer Center, Tulane University School of Medicine, New Orleans, Louisiana 70112, USA.,Department of Oncology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China
| | - Xiang Zhou
- Department of Biochemistry &Molecular Biology, Tulane University School of Medicine, New Orleans, Louisiana 70112, USA.,Tulane Cancer Center, Tulane University School of Medicine, New Orleans, Louisiana 70112, USA
| | - Bo Cao
- Department of Biochemistry &Molecular Biology, Tulane University School of Medicine, New Orleans, Louisiana 70112, USA.,Tulane Cancer Center, Tulane University School of Medicine, New Orleans, Louisiana 70112, USA
| | - Peng Liao
- Department of Biochemistry &Molecular Biology, Tulane University School of Medicine, New Orleans, Louisiana 70112, USA.,Tulane Cancer Center, Tulane University School of Medicine, New Orleans, Louisiana 70112, USA
| | - Hongbing Liu
- Department of Biochemistry &Molecular Biology, Tulane University School of Medicine, New Orleans, Louisiana 70112, USA
| | - Yun Chen
- Department of Biochemistry &Molecular Biology, Tulane University School of Medicine, New Orleans, Louisiana 70112, USA
| | - Hee-Won Park
- Department of Biochemistry &Molecular Biology, Tulane University School of Medicine, New Orleans, Louisiana 70112, USA
| | - Shelya X Zeng
- Department of Biochemistry &Molecular Biology, Tulane University School of Medicine, New Orleans, Louisiana 70112, USA.,Tulane Cancer Center, Tulane University School of Medicine, New Orleans, Louisiana 70112, USA
| | - Hua Lu
- Department of Biochemistry &Molecular Biology, Tulane University School of Medicine, New Orleans, Louisiana 70112, USA.,Tulane Cancer Center, Tulane University School of Medicine, New Orleans, Louisiana 70112, USA
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29
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Association between nuclear expression of retinoic acid receptor alpha and beta and clinicopathological features and prognosis of advanced non-small cell lung cancer. Int J Clin Oncol 2016; 21:1051-1061. [PMID: 27306217 DOI: 10.1007/s10147-016-1002-0] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/24/2015] [Accepted: 06/02/2016] [Indexed: 02/06/2023]
Abstract
BACKGROUND Transcription factors such as retinoic acid receptor alpha (RARα) and beta (RARβ) and Yin Yang 1 (YY1) are associated with the progression of non-small cell lung cancer (NSCLC). In particular, a lack of RARβ expression is associated with NSCLC development. The aim of this study was to analyze the expression of RARα, RARβ and YY1 and their relationship with prognosis in patients with advanced NSCLC. METHODS The expression of RARα, RARβ and YY1 was assessed by immunohistochemistry and quantitative computerized image software. RESULTS Eighty-five patients treated with platinum-based chemotherapy were included in the analysis. The mean and standard deviation of the nuclear expression of RARα, RARβ and YY1 were 184.5 ± 124.4, 18 ± 27 and 16.6 ± 20.5, respectively. The nuclear expression of RARβ was associated with the nuclear expression of YY1 (R 2 = 0.28; p value < 0.0001). Patients with high nuclear expression of YY1 were likely to be non-smokers (61.9 vs 40.5 %). Median progression-free survival (PFS) was 5.9 months (3.48-8.28). Low expression of RARα was independently associated with worse PFS following chemotherapy (10.3 vs 5.46 months p = 0.040). Median overall survival (OS) was 15.6 months (4.5-26.7), and lower nuclear expression of RARβ was independently associated with shorter OS (27.5 vs 8.7 months; p = 0.037). CONCLUSION Our study suggests that the loss of RARs is associated with a worse prognosis and these receptors could be a potential molecular target for NSCLC.
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30
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PP2A inhibitors arrest G2/M transition through JNK/Sp1- dependent down-regulation of CDK1 and autophagy-dependent up-regulation of p21. Oncotarget 2016; 6:18469-83. [PMID: 26053095 PMCID: PMC4621904 DOI: 10.18632/oncotarget.4063] [Citation(s) in RCA: 31] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/14/2015] [Accepted: 05/14/2015] [Indexed: 01/07/2023] Open
Abstract
Protein phosphatase 2A (PP2A) plays an important role in the control of the cell cycle. We previously reported that the PP2A inhibitors, cantharidin and okadaic acid (OA), efficiently repressed the growth of cancer cells. In the present study, we found that PP2A inhibitors arrested the cell cycle at the G2 phase through a mechanism that was dependent on the JNK pathway. Microarrays further showed that PP2A inhibitors induced expression changes in multiple genes that participate in cell cycle transition. To verify whether these expression changes were executed in a PP2A-dependent manner, we targeted the PP2A catalytic subunit (PP2Ac) using siRNA and evaluated gene expression with a microarray. After the cross comparison of these microarray data, we identified that CDK1 was potentially the same target when treated with either PP2A inhibitors or PP2Ac siRNA. In addition, we found that the down-regulation of CDK1 occurred in a JNK-dependent manner. Luciferase reporter gene assays demonstrated that repression of the transcription of CDK1 was executed through the JNK-dependent activation of the Sp1 transcription factor. By constructing deletion mutants of the CDK1 promoter and by using ChIP assays, we identified an element in the CDK1 promoter that responded to the JNK/Sp1 pathway after stimulation with PP2A inhibitors. Cantharidin and OA also up-regulated the expression of p21, an inhibitor of CDK1, via autophagy rather than PP2A/JNK pathway. Thus, this present study found that the PP2A/JNK/Sp1/CDK1 pathway and the autophagy/p21 pathway participated in G2/M cell cycle arrest triggered by PP2A inhibitors.
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31
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Tiloke C, Phulukdaree A, Anand K, Gengan RM, Chuturgoon AA. Moringa oleiferaGold Nanoparticles Modulate Oncogenes, Tumor Suppressor Genes, and Caspase-9 Splice Variants in A549 Cells. J Cell Biochem 2016; 117:2302-14. [DOI: 10.1002/jcb.25528] [Citation(s) in RCA: 54] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/21/2015] [Accepted: 02/25/2016] [Indexed: 01/17/2023]
Affiliation(s)
- Charlette Tiloke
- Discipline of Medical Biochemistry and Chemical Pathology; School of Laboratory Medicine and Medical Sciences; College of Health Sciences; University of KwaZulu-Natal; Congella Durban 4013 South Africa
| | - Alisa Phulukdaree
- Discipline of Medical Biochemistry and Chemical Pathology; School of Laboratory Medicine and Medical Sciences; College of Health Sciences; University of KwaZulu-Natal; Congella Durban 4013 South Africa
- Department of Physiology; School of Medicine; Faculty of Health Sciences; University of Pretoria; Pretoria South Africa
| | - Krishnan Anand
- Department of Chemistry; Faculty of Applied Sciences; Durban University of Technology; Durban 4001 South Africa
| | - Robert M. Gengan
- Department of Chemistry; Faculty of Applied Sciences; Durban University of Technology; Durban 4001 South Africa
| | - Anil A. Chuturgoon
- Discipline of Medical Biochemistry and Chemical Pathology; School of Laboratory Medicine and Medical Sciences; College of Health Sciences; University of KwaZulu-Natal; Congella Durban 4013 South Africa
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32
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Jung JH, Liao JM, Zhang Q, Zeng S, Nguyen D, Hao Q, Zhou X, Cao B, Kim SH, Lu H. Inauhzin(c) inactivates c-Myc independently of p53. Cancer Biol Ther 2016; 16:412-9. [PMID: 25692307 DOI: 10.1080/15384047.2014.1002698] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022] Open
Abstract
Oncogene MYC is deregulated in many human cancers, especially in lymphoma. Previously, we showed that inauhzin (INZ) activates p53 and inhibits tumor growth. However, whether INZ could suppress cancer cell growth independently of p53 activity is still elusive. Here, we report that INZ(c), a second generation of INZ, suppresses c-Myc activity and thus inhibits growth of human lymphoma cells in a p53-independent manner. INZ(c) treatment decreased c-Myc expression at both mRNA and protein level, and suppressed c-Myc transcriptional activity in human Burkitt's lymphoma Raji cells with mutant p53. Also, we showed that overexpressing ectopic c-Myc rescues the inhibition of cell proliferation by INZ(c) in Raji cells, implicating c-Myc activity is targeted by INZ(c). Interestingly, the effect of INZ(c) on c-Myc expression was impaired by disrupting the targeting of c-Myc mRNA by miRNAs via knockdown of ribosomal protein (RP) L5, RPL11, or Ago2, a subunit of RISC complex, indicating that INZ(c) targets c-Myc via miRNA pathways. These results reveal a new mechanism that INZ
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Key Words
- Dox, doxorubicin
- FACS, Fluorescence-activated cell sorting
- GTP, guanosine triphosphate
- INZ, inauhzin
- Inauhzin
- MTT, 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide
- PBS, Phosphate Buffered Saline
- PI, propidium iodide
- RISC, RNA-induced silencing complex
- RP, ribosomal protein
- RPL11
- RPL5
- UTR, untranslated region
- c-Myc
- lymphoma
- microRNA
- q-RT-PCR, Real-time reverse transcription polymerase chain reaction
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Affiliation(s)
- Ji Hoon Jung
- a Department of Biochemistry & Molecular Biology and Cancer Center ; Tulane University School of Medicine ; New Orleans , LA USA
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Huang H, Ma L, Li J, Yu Y, Zhang D, Wei J, Jin H, Xu D, Gao J, Huang C. NF-κB1 inhibits c-Myc protein degradation through suppression of FBW7 expression. Oncotarget 2015; 5:493-505. [PMID: 24457827 PMCID: PMC3964224 DOI: 10.18632/oncotarget.1643] [Citation(s) in RCA: 39] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/29/2023] Open
Abstract
NF-κB is a well-known transcription factor in regulation of multiple gene transcription and biological processes, and most of them are relied on its transcriptional activity of the p65/RelA subunit, while biological function of another ubiquitously expressed subunit NF-κB1 (p50) remains largely unknown due to lack transcriptional activation domain. Here we discovered a novel biological function of p50 as a regulator of oncogenic c-Myc protein degradation upon arsenite treatment in a NF-κB transcriptional-independent mechanism. Our results found that p50 was crucial for c-Myc protein induction following arsenite treatment by using specific knockdown and deletion of p50 in its normal expressed cells as well as reconstituting expression of p50 in its deficient cells. Subsequently we showed that p50 upregulated c-Myc protein expression mainly through inhibiting its degradation. We also identified that p50 exhibited this novel property by suppression of FBW7 expression. FBW7 was profoundly upregulated in p50-defecient cells in comparison to that in p50 intact cells, whereas knockdown of FBW7 in p50-/- cells restored arsenite-induced c-Myc protein accumulation, assuring that FBW7 up-regulation was responsible for defect of c-Myc protein expression in p50-/- cells. In addition, we discovered that p50 suppressed fbw7 gene transcription via inhibiting transcription factor E2F1 transactivation. Collectively, our studies demonstrated a novel function of p50 as a regulator of c-Myc protein degradation, contributing to our notion that p50-regulated protein expression through multiple levels at protein translation and degradation, further providing a significant insight into the understanding of biomedical significance of p50 protein.
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Affiliation(s)
- Haishan Huang
- Zhejiang Provincial Key Laboratory for Technology and Application of Model Organisms, School of Life Sciences, Wenzhou Medical University, Wenzhou, Zhejiang, China
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Devine T, Dai MS. Targeting the ubiquitin-mediated proteasome degradation of p53 for cancer therapy. Curr Pharm Des 2013; 19:3248-62. [PMID: 23151129 DOI: 10.2174/1381612811319180009] [Citation(s) in RCA: 49] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/02/2012] [Accepted: 11/01/2012] [Indexed: 02/08/2023]
Abstract
Within the past decade, there has been a revolution in the types of drugs developed to treat cancer. Therapies that selectively target cancer-specific aberrations, such as kinase inhibitors, have made a dramatic impact on a subset of patients. In spite of these successes, there is still a dearth of treatment options for the vast majority of patients. Therefore, there is a need to design therapies with broader efficacy. The p53 tumor suppressor pathway is one of the most frequently altered in human cancers. However, about half of all cancers retain wild-type p53, yet through various mechanisms, the p53 pathway is otherwise inactivated. Targeting this pathway for reactivation truly represents the "holy grail" in cancer treatment. Most commonly, destabilization of p53 by various components of ubiquitin- proteasome system, notably the ubiquitin ligase MDM2 and its partner MDMX as well as various deubiquitinating enzymes (DUBs), render p53 inert and unresponsive to stress signals. Reinstating its function in cancer has been a long sought-after goal. Towards this end, a great deal of work has been devoted to the development of compounds that either interfere with the p53-MDM2 and p53- MDMX interactions, inhibit MDM2 E3 activity, or target individual DUBs. Here we review the current progress that has been made in the field, with a special emphasis on both MDM2 and DUB inhibitors. Developing inhibitors targeting the upstream of the p53 ubiquitination pathway will likely also be a valuable option.
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Affiliation(s)
- Tiffany Devine
- Department of Molecular & Medical Genetics, Oregon Health & Science University, 3181 SW Sam Jackson Park Road, Portland, OR 97239, USA
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35
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Zhou X, Hao Q, Liao JM, Liao P, Lu H. Ribosomal protein S14 negatively regulates c-Myc activity. J Biol Chem 2013; 288:21793-801. [PMID: 23775087 PMCID: PMC3724636 DOI: 10.1074/jbc.m112.445122] [Citation(s) in RCA: 69] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/17/2012] [Revised: 05/16/2013] [Indexed: 12/13/2022] Open
Abstract
The ribosomal gene RPS14 is associated with the cancer-prone 5q-syndrome, which is caused by an interstitial deletion of the long arm of human chromosome 5. Previously, we found that ribosomal protein S14 (RPS14) binds to and inactivates MDM2, consequently leading to p53-dependent cell-cycle arrest and growth inhibition. However, it remains elusive whether RPS14 regulates cell proliferation in a p53-independent manner. Here, we show that RPS14 interacts with the Myc homology box II (MBII) and the C-terminal basic helix-loop-helix leucine zipper (bHLH-LZ) domains of the oncoprotein c-Myc. Further, RPS14 inhibited c-Myc transcriptional activity by preventing the recruitment of c-Myc and its cofactor, TRRAP, to the target gene promoters, as thus suppressing c-Myc-induced cell proliferation. Also, siRNA-mediated RPS14 depletion elevated c-Myc transcriptional activity determined by its target gene, Nucleolin, expression. Interestingly, RPS14 depletion also resulted in the induction of c-Myc mRNA and subsequent protein levels. Consistent with this, RPS14 promoted c-Myc mRNA turnover through an Argonaute 2 (Ago2)- and microRNA-mediated pathway. Taken together, our study demonstrates that RPS14 negates c-Myc functions by directly inhibiting its transcriptional activity and mediating its mRNA degradation via miRNA.
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Affiliation(s)
- Xiang Zhou
- From the Department of Biochemistry & Molecular Biology and Cancer Center, Tulane University School of Medicine, New Orleans, Louisiana 70112
| | - Qian Hao
- From the Department of Biochemistry & Molecular Biology and Cancer Center, Tulane University School of Medicine, New Orleans, Louisiana 70112
| | - Jun-ming Liao
- From the Department of Biochemistry & Molecular Biology and Cancer Center, Tulane University School of Medicine, New Orleans, Louisiana 70112
| | - Peng Liao
- From the Department of Biochemistry & Molecular Biology and Cancer Center, Tulane University School of Medicine, New Orleans, Louisiana 70112
| | - Hua Lu
- From the Department of Biochemistry & Molecular Biology and Cancer Center, Tulane University School of Medicine, New Orleans, Louisiana 70112
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36
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Xu W, Banerji S, Davie JR, Kassie F, Yee D, Kratzke R. Yin Yang gene expression ratio signature for lung cancer prognosis. PLoS One 2013; 8:e68742. [PMID: 23874744 PMCID: PMC3714286 DOI: 10.1371/journal.pone.0068742] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/15/2013] [Accepted: 06/03/2013] [Indexed: 01/03/2023] Open
Abstract
Many studies have established gene expression-based prognostic signatures for lung cancer. All of these signatures were built from training data sets by learning the correlation of gene expression with the patients' survival time. They require all new sample data to be normalized to the training data, ultimately resulting in common problems of low reproducibility and impracticality. To overcome these problems, we propose a new signature model which does not involve data training. We hypothesize that the imbalance of two opposing effects in lung cancer cells, represented by Yin and Yang genes, determines a patient's prognosis. We selected the Yin and Yang genes by comparing expression data from normal lung and lung cancer tissue samples using both unsupervised clustering and pathways analyses. We calculated the Yin and Yang gene expression mean ratio (YMR) as patient risk scores. Thirty-one Yin and thirty-two Yang genes were identified and selected for the signature development. In normal lung tissues, the YMR is less than 1.0; in lung cancer cases, the YMR is greater than 1.0. The YMR was tested for lung cancer prognosis prediction in four independent data sets and it significantly stratified patients into high- and low-risk survival groups (p = 0.02, HR = 2.72; p = 0.01, HR = 2.70; p = 0.007, HR = 2.73; p = 0.005, HR = 2.63). It also showed prediction of the chemotherapy outcomes for stage II & III. In multivariate analysis, the YMR risk factor was more successful at predicting clinical outcomes than other commonly used clinical factors, with the exception of tumor stage. The YMR can be measured in an individual patient in the clinic independent of gene expression platform. This study provided a novel insight into the biology of lung cancer and shed light on the clinical applicability.
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Affiliation(s)
- Wayne Xu
- Manitoba Institute of Cell Biology, University of Manitoba, Winnipeg, Canada.
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37
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Chandra S, Priyadarshini R, Madhavan V, Tikoo S, Hussain M, Mudgal R, Modi P, Srivastava V, Sengupta S. Enhancement of c-Myc degradation by BLM helicase leads to delayed tumor initiation. J Cell Sci 2013; 126:3782-95. [PMID: 23750012 DOI: 10.1242/jcs.124719] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/19/2022] Open
Abstract
The spectrum of tumors that arise owing to the overexpression of c-Myc and loss of BLM is very similar. Hence, it was hypothesized that the presence of BLM negatively regulates c-Myc functions. By using multiple isogenic cell lines, we observed that the decrease of endogenous c-Myc levels that occurs in the presence of BLM is reversed when the cells are treated with proteasome inhibitors, indicating that BLM enhances c-Myc turnover. Whereas the N-terminal region of BLM interacts with c-Myc, the rest of the helicase interacts with the c-Myc E3 ligase Fbw7. The two BLM domains act as 'clamp and/or adaptor', enhancing the binding of c-Myc to Fbw7. BLM promotes Fbw7-dependent K48-linked c-Myc ubiquitylation and its subsequent degradation in a helicase-independent manner. A subset of BLM-regulated genes that are also targets of c-Myc were determined and validated at both RNA and protein levels. To obtain an in vivo validation of the effect of BLM on c-Myc-mediated tumor initiation, isogenic cells from colon cancer cells that either do or do not express BLM had been manipulated to block c-Myc expression in a controlled manner. By using these cell lines, the metastatic potential and rate of initiation of tumors in nude mice were determined. The presence of BLM decreases c-Myc-mediated invasiveness and delays tumor initiation in a mouse xenograft model. Consequently, in tumors that express BLM but not c-Myc, we observed a decreased ratio of proliferation to apoptosis together with a suppressed expression of the angiogenesis marker CD31. Hence, partly owing to its regulation of c-Myc stability, BLM acts as a 'caretaker tumor suppressor'.
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Affiliation(s)
- Suruchika Chandra
- National Institute of Immunology, Aruna Asaf Ali Marg, New Delhi 110067, India
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38
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Tam B, Salamon A, Bajtai A, Németh A, Kiss J, Simon L, Molnár T. The real face of juvenile polyposis syndrome. J Gastrointest Oncol 2012. [PMID: 23205314 DOI: 10.3978/j.issn.2078-6891.2012.032] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/14/2022] Open
Abstract
Colorectal cancers are mostly sporadic; some cases of familial clustering and autosomal dominant conditions are also known to occur. Juvenile polyposis syndrome (JPS) is an autosomal dominant condition caused by the mutation of the SMAD4 or the BMPR1A genes. JPS is characterized by hamartomatous polyps developing in the upper and lower intestine. Contradicting previous studies, many of these polyps can go through malignant transformation.This paper reports the case of a male patient who was continuously treated for juvenile polyposis. During the eighteen years of treatment, more than hundred polyps were endoscopically removed from his gastrointestinal tract. The patient's care was interrupted for eight years due to insufficient compliance. He was subsequently referred to our Department of Gastroenterology in severe clinical condition caused by metastatic colorectal cancer. He died after a short palliative therapy at the age of 31. His first-degree accessible relatives were further examined for juvenile polyposis syndrome. Several gastrointestinal polyps of different histological origin were observed in the deceased patient's brother, who subsequently had to undergo a left lateral hemicolectomy. Genetic analyses revealed mutations of the BMPR1A gene in the clinically affected brother, the brother's daughter, and in the deceased proband's daughter.Indebt genetic analyses helped customize and deliver care to a very specific group of individuals. We were able to identify potential family members on whom preventive care and treatment could be focused and simultaneously prevented unnecessary clinical and invasive procedures on those who were healthy. Furthermore, these analyses helped prevent future unnecessary trauma or distress on the analyzed family.
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Affiliation(s)
- Beatrix Tam
- Department of Gastroenterology, Tolna County Teaching Hospital, Szekszárd, Hungary
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39
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Landry BD, Doyle JP, Toczyski DP, Benanti JA. F-box protein specificity for g1 cyclins is dictated by subcellular localization. PLoS Genet 2012; 8:e1002851. [PMID: 22844257 PMCID: PMC3405998 DOI: 10.1371/journal.pgen.1002851] [Citation(s) in RCA: 35] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/01/2012] [Accepted: 06/06/2012] [Indexed: 01/16/2023] Open
Abstract
Levels of G1 cyclins fluctuate in response to environmental cues and couple mitotic signaling to cell cycle entry. The G1 cyclin Cln3 is a key regulator of cell size and cell cycle entry in budding yeast. Cln3 degradation is essential for proper cell cycle control; however, the mechanisms that control Cln3 degradation are largely unknown. Here we show that two SCF ubiquitin ligases, SCF(Cdc4) and SCF(Grr1), redundantly target Cln3 for degradation. While the F-box proteins (FBPs) Cdc4 and Grr1 were previously thought to target non-overlapping sets of substrates, we find that Cdc4 and Grr1 each bind to all 3 G1 cyclins in cell extracts, yet only Cln3 is redundantly targeted in vivo, due in part to its nuclear localization. The related cyclin Cln2 is cytoplasmic and exclusively targeted by Grr1. However, Cdc4 can interact with Cdk-phosphorylated Cln2 and target it for degradation when cytoplasmic Cdc4 localization is forced in vivo. These findings suggest that Cdc4 and Grr1 may share additional redundant targets and, consistent with this possibility, grr1Δ cdc4-1 cells demonstrate a CLN3-independent synergistic growth defect. Our findings demonstrate that structurally distinct FBPs are capable of interacting with some of the same substrates; however, in vivo specificity is achieved in part by subcellular localization. Additionally, the FBPs Cdc4 and Grr1 are partially redundant for proliferation and viability, likely sharing additional redundant substrates whose degradation is important for cell cycle progression.
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Affiliation(s)
- Benjamin D. Landry
- Program in Gene Function and Expression, University of Massachusetts Medical School, Worcester, Massachusetts, United States of America
- Program in Molecular Medicine, University of Massachusetts Medical School, Worcester, Massachusetts, United States of America
| | - John P. Doyle
- Department of Biochemistry and Biophysics, University of California San Francisco, San Francisco, California, United States of America
| | - David P. Toczyski
- Department of Biochemistry and Biophysics, University of California San Francisco, San Francisco, California, United States of America
| | - Jennifer A. Benanti
- Program in Gene Function and Expression, University of Massachusetts Medical School, Worcester, Massachusetts, United States of America
- Program in Molecular Medicine, University of Massachusetts Medical School, Worcester, Massachusetts, United States of America
- * E-mail:
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40
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Benassi B, Flavin R, Marchionni L, Zanata S, Pan Y, Chowdhury D, Marani M, Strano S, Muti P, Blandino G, Loda M. MYC is activated by USP2a-mediated modulation of microRNAs in prostate cancer. Cancer Discov 2012; 2:236-47. [PMID: 22585994 DOI: 10.1158/2159-8290.cd-11-0219] [Citation(s) in RCA: 73] [Impact Index Per Article: 5.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/26/2022]
Abstract
UNLABELLED Ubiquitin-specific protease 2a (USP2a) is overexpressed in almost half of human prostate cancers and c-Myc is amplified in one third of these tumor types. Transgenic MYC expression drives invasive adenocarcinomas in the murine prostate. We show that overexpression of USP2a downregulates a set of microRNAs that collectively increase MYC levels by MDM2 deubiquitination and subsequent p53 inactivation. By establishing MYC as a target of miR-34b/c, we demonstrate that this cluster functions as a tumor suppressor in prostate cancer cells. We identify a distinct mRNA signature that is enriched for MYC-regulated transcripts and transcription factor binding sites in USP2a overexpressing prostate cancer cells. We demonstrate that these genes are associated with an invasive phenotype in human prostate cancer and that the proliferative and invasive properties of USP2a overexpressing cells are MYC-dependent. These results highlight an unrecognized mechanism of MYC regulation in prostate cancer and suggest alternative therapeutic strategies in targeting MYC. SIGNIFICANCE The deubiquitinating enzyme USP2a has previously been shown to be oncogenic, overexpressed in almost half of human prostate adenocarcinomas, and prolongs the half-life of targets such as fatty acid synthase, MDM2, and cyclin D1. Here, we highlight a new mechanism by which USP2a enhances MYC levels through the modulation of specific subsets of microRNAs in prostate cancer, suggesting alternative therapeutic strategies for targeting MYC.
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Affiliation(s)
- Barbara Benassi
- Translational Oncogenomics Unit, Regina Elena Cancer Institute, Rome, Italy
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41
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Vurusaner B, Poli G, Basaga H. Tumor suppressor genes and ROS: complex networks of interactions. Free Radic Biol Med 2012; 52:7-18. [PMID: 22019631 DOI: 10.1016/j.freeradbiomed.2011.09.035] [Citation(s) in RCA: 227] [Impact Index Per Article: 17.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/10/2011] [Revised: 09/27/2011] [Accepted: 09/29/2011] [Indexed: 12/24/2022]
Abstract
Tumor suppressor genes regulate diverse cellular activities including DNA damage repair, cell cycle arrest, mitogenic signaling, cell differentiation, migration, and programmed cell death. In this review the tumor suppressor genes p53, FoxO, retinoblastoma (RB), p21, p16, and breast cancer susceptibility genes 1 and 2 (BRCA1 and BRCA2) and their roles in oxidative stress are summarized with a focus on the links and interplay between their pathways and reactive oxygen species (ROS). The results of a number of studies have demonstrated an antioxidant role for tumor suppressor proteins, activating the expression of some well-known antioxidant genes in response to oxidative stress. On the other hand, recent studies have revealed a pro-oxidant role for p53 by which cellular ROS are increased by enhanced transcription of proapoptotic genes. A tightly regulated feedback loop between ROS and FoxO proteins, with ROS regulating FoxO activity through posttranslational modifications and protein interactions and FoxO controlling intracellular ROS levels, has been demonstrated. Furthermore, these studies have shown that FoxO transcription factors and p38 mitogen-activated protein kinases may interact with the RB pathway under stress conditions. In addition, cellular senescence studies established an unexpected role for ROS in inducing and maintaining senescence-induced tumor suppression that blocks cytokinesis to ensure senescent cells never divide again. p21 and p16 have been shown to act as tumor suppressor proteins and this function extends beyond cell cycle control and includes important roles in regulating oxidative stress. Consequently, these important interactions indicate a critical potential role for tumor suppressor genes in the cellular response against oxidative stress and emphasize links between ROS and tumor suppressor genes that might be therapeutic targets in oxidative damage-associated diseases.
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Affiliation(s)
- Beyza Vurusaner
- Biological Sciences and Bioengineering Program, Faculty of Natural Sciences and Engineering, Sabanci University, Istanbul, Turkey
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42
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Positive regulation of p53 stability and activity by the deubiquitinating enzyme Otubain 1. EMBO J 2011; 31:576-92. [PMID: 22124327 DOI: 10.1038/emboj.2011.434] [Citation(s) in RCA: 164] [Impact Index Per Article: 11.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/30/2011] [Accepted: 11/08/2011] [Indexed: 12/19/2022] Open
Abstract
The ubiquitin (Ub)-proteasome system plays a pivotal role in the regulation of p53 protein stability and activity. p53 is ubiquitinated and destabilized by MDM2 and several other Ub E3s, whereas it is deubiquitinated and stabilized by Ub-specific protease (USP)7 and USP10. Here we show that the ovarian tumour domain-containing Ub aldehyde-binding protein 1 (Otub1) is a novel p53 regulator. Otub1 directly suppresses MDM2-mediated p53 ubiquitination in cells and in vitro. Overexpression of Otub1 drastically stabilizes and activates p53, leading to apoptosis and marked inhibition of cell proliferation in a p53-dependent manner. These effects are independent of its catalytic activity but require residue Asp88. Mutation of Asp88 to Ala (Otub1(D88A)) abolishes activity of Otub1 to suppress p53 ubiquitination. Further, wild-type Otub1 and its catalytic mutant (Otub1(C91S)), but not Otub1(D88A), bind to the MDM2 cognate E2, UbcH5, and suppress its Ub-conjugating activity in vitro. Overexpression of Otub1(D88A) or ablation of endogenous Otub1 by siRNA markedly impaired p53 stabilization and activation in response to DNA damage. Together, these results reveal a novel function for Otub1 in regulating p53 stability and activity.
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43
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Li W, Chen Z, Gong FR, Zong Y, Chen K, Li DM, Yin H, Duan WM, Miao Y, Tao M, Han X, Xu ZK. Growth of the pancreatic cancer cell line PANC-1 is inhibited by protein phosphatase 2A inhibitors through overactivation of the c-Jun N-terminal kinase pathway. Eur J Cancer 2011; 47:2654-64. [PMID: 21958460 DOI: 10.1016/j.ejca.2011.08.014] [Citation(s) in RCA: 37] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/20/2011] [Revised: 06/22/2011] [Accepted: 08/20/2011] [Indexed: 12/24/2022]
Abstract
Protein phosphatase 2A (PP2A) is a multimeric serine/threonine phosphatase that can dephosphorylate multiple kinases. It is generally considered to be a cancer suppressor as its inhibition can induce phosphorylation and activation of substrate kinases that mainly accelerate growth. We previously reported that cantharidin, an active constituent of a traditional Chinese medicine, potently and selectively inhibited PP2A, yet efficiently repressed the growth of pancreatic cancer cells through activation of the c-Jun N-terminal kinase (JNK) pathway. This suggested that activation of kinase pathways might also be a potential strategy for cancer therapy. In this study, we have confirmed that the basal activity of the phospatidylinositol 3-kinase (PI3K)/JNK/activator protein 1 (AP-1) pathway promoted pancreatic cancer cell growth when stimulated by growth factors. Interestingly, although treatment with the PP2A inhibitors, cantharidin or okadaic acid (OA), amplified the PI3K-dependent activation of JNK, cell growth was repressed. We therefore hypothesised that a specific level of activity of the JNK pathway might be required to maintain the promitogenic function, as both repression and overactivation of JNK could inhibit cell proliferation. It was found that the JNK-dependent growth inhibition was independent of the activation of AP-1, but dependent on the repression of Akt. Although the PP2A inhibitors triggered overactivation of JNK and inhibited cell growth, excessively activated protein kinase C (PKC) improved cell survival. Combined treatment with a PP2A inhibitor and a PKC inhibitor produced a synergistic effect, which indicates a potentially promising therapeutic approach to pancreatic cancer treatment.
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Affiliation(s)
- Wei Li
- Department of General Surgery, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China
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44
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Paek H, Hwang JY, Zukin RS, Hébert JM. β-Catenin-dependent FGF signaling sustains cell survival in the anterior embryonic head by countering Smad4. Dev Cell 2011; 20:689-99. [PMID: 21571225 DOI: 10.1016/j.devcel.2011.04.010] [Citation(s) in RCA: 25] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/02/2010] [Revised: 03/02/2011] [Accepted: 04/26/2011] [Indexed: 12/22/2022]
Abstract
Growing evidence suggests that FGFs secreted from embryonic signaling centers are key mediators of cell survival. However, the mechanisms regulating FGF-dependent cell survival remain obscure. At the rostral end of the embryo, for example, ablation of FGF signaling leads to the rapid death of the precursor cells that form the anterior head, including the telencephalon. Here, we outline a core genetic circuit that regulates survival in the embryonic mouse head: WNT signaling through β-catenin directly maintains FGF expression and requires FGF function in vivo to oppose proapoptotic TGF-β signaling through SMAD4. Moreover, these antagonistic pathways converge on the transcriptional regulation of apoptosis, and genes such as Cdkn1a, suggesting a mechanism for how signaling centers in the embryonic head regulate cell survival.
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Affiliation(s)
- Hunki Paek
- Department of Genetics, Albert Einstein College of Medicine, Bronx, NY 10461, USA
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45
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Antitumor activity of erythromycin on human neuroblastoma cell line (SH-SY5Y). ACTA ACUST UNITED AC 2011; 31:33-38. [PMID: 21336720 DOI: 10.1007/s11596-011-0146-4] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/10/2010] [Indexed: 12/18/2022]
Abstract
Antitumor effects of erythromycin and the related mechanism were investigated in the present study. Neuroblastoma cells (SH-SY5Y) were exposed to erythromycin at different concentrations for different durations. Cell proliferation was measured by cell counting, and cell viability was examined by MTT assay. Cell cycle phase distribution and the cytosolic calcium level were detected by flow cytometry. Mitochondrial membrane potential was measured by the JC-1 probe staining and fluorescent microscopy. The expression of an oncogene (c-Myc) and a tumor suppressor [p21 (WAF1/Cip1)] proteins was analyzed by using Western blotting. Erythromycin could inhibit the proliferation of SH-SY5Y cells in a concentration- and time-dependent manner. The cell cycle was arrested at S phase. Mitochondrial membrane potential collapsed and the cytosolic calcium was overloaded in SH-SY5Y cells when treated with erythromycin. The expression of c-Myc protein was down-regulated, while that of p21 (WAF1/Cip1) protein was up-regulated. It was concluded that erythromycin could restrain the proliferation of SH-SY5Y cells. The antitumor mechanism of erythromycin might involve regulating the expression of c-Myc and p21 (WAF1/Cip1) proteins.
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46
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Agrawal P, Yu K, Salomon AR, Sedivy JM. Proteomic profiling of Myc-associated proteins. Cell Cycle 2010; 9:4908-21. [PMID: 21150319 DOI: 10.4161/cc.9.24.14199] [Citation(s) in RCA: 53] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022] Open
Abstract
Mammalian c-Myc is a member of a small family of three closely related transcription factors. The Myc family of proto-oncogenes are among the most potent activators of tumorigenesis, and are frequently overexpressed in diverse cancers. c-Myc has an unusually broad array of regulatory functions, which include, in addition to roles in the cell cycle and apoptosis, effects on a variety of metabolic functions, cell differentiation, senescence, and stem cell maintenance. A significant number of c-Myc interacting proteins have already been defined, but it is widely believed that the c-Myc interactome is vastly larger than currently documented. In addition to interactions with components of the transcription machinery, transcription independent nuclear interactions with the DNA replication and RNA processing pathways have been reported. Cytoplasmic roles of c-Myc have also been recently substantiated. Recent advances in proteomics have opened new possibilities for the isolation of protein complexes under native conditions and confidently identifying the components using ultrasensitive, high mass accuracy and high resolution mass spectrometry techniques. In this communication we report a new tandem affinity purification (TAP) c-Myc interaction screen that employed new cell lines with near-physiological levels of c-Myc expression with multi-dimensional protein identification techniques (MudPIT) for the detection and quantification of proteins. Both label-free and the recently developed stable isotope labeling with amino acids in cell culture (SILAC) methodologies were used. Combined data from multiple biological replicates provided a dataset of 418 non-redundant proteins, 389 of which are putative novel interactors. This new information should significantly advance our understanding of this interesting and important master regulator.
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Affiliation(s)
- Pooja Agrawal
- Department of Molecular Biology, Cell Biology and Biochemistry, Brown University, Providence, RI, USA
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47
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Rubenstein EM, Hochstrasser M. Redundancy and variation in the ubiquitin-mediated proteolytic targeting of a transcription factor. Cell Cycle 2010; 9:4282-5. [PMID: 20980825 DOI: 10.4161/cc.9.21.13741] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/19/2022] Open
Abstract
As central components of the intricate networks of eukaryotic gene regulation, transcription factors are frequent targets of ubiquitin-dependent proteolysis. A well-known example is the budding yeast MATα2 (α2) transcriptional repressor, which functions as a master regulator of cell-type determination. Degradation of α2 by the ubiquitin-proteasome system is necessary for a phenotypic switch from one cell type to another. A surprisingly complex set of ubiquitin-protein conjugation mechanisms are involved. One pathway utilizes an integral-membrane ubiquitin ligase (E3) that also functions in endoplasmic reticulum-associated degradation (ERAD). Recently, we showed that a second α2 ubiquitylation pathway uses a heterodimeric E3 that, while able to bind the ubiquitin-like protein SUMO, directly recognizes non-sumoylated α2. Other transcription factors are now also known to be ubiquitylated by multiple mechanisms; as many as a dozen E3s have been implicated in degradation of the human p53 tumor suppressor, for example. We discuss general issues of redundancy and mechanistic variation in protein modification by ubiquitin.
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Affiliation(s)
- Eric M Rubenstein
- Department of Molecular Biophysics & Biochemistry, Yale University, New Haven, CT, USA
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Macias E, Jin A, Deisenroth C, Bhat K, Mao H, Lindström MS, Zhang Y. An ARF-independent c-MYC-activated tumor suppression pathway mediated by ribosomal protein-Mdm2 Interaction. Cancer Cell 2010; 18:231-43. [PMID: 20832751 PMCID: PMC4400806 DOI: 10.1016/j.ccr.2010.08.007] [Citation(s) in RCA: 166] [Impact Index Per Article: 11.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/20/2010] [Revised: 05/24/2010] [Accepted: 07/13/2010] [Indexed: 01/10/2023]
Abstract
In vitro studies have shown that inhibition of ribosomal biogenesis can activate p53 through ribosomal protein (RP)-mediated suppression of Mdm2 E3 ligase activity. To study the physiological significance of the RP-Mdm2 interaction, we generated mice carrying a cancer-associated cysteine-to-phenylalanine substitution in the zinc finger of Mdm2 that disrupted its binding to RPL5 and RPL11. Mice harboring this mutation, retain normal p53 response to DNA damage, but lack of p53 response to perturbations in ribosome biogenesis. Loss of RP-Mdm2 interaction significantly accelerates Eμ-Myc-induced lymphomagenesis. Furthermore, ribosomal perturbation-induced p53 response does not require tumor suppressor p19ARF. Collectively, our findings establish RP-Mdm2 interaction as a genuine p53 stress-signaling pathway activated by aberrant ribosome biogenesis and essential for safeguarding against oncogenic c-MYC-induced tumorigenesis.
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Affiliation(s)
- Everardo Macias
- Department of Radiation Oncology, School of Medicine, the University of North Carolina at Chapel Hill, Chapel Hill, NC.
- Lineberger Comprehensive Cancer Center, School of Medicine, the University of North Carolina at Chapel Hill, Chapel Hill, NC.
| | - Aiwen Jin
- Department of Radiation Oncology, School of Medicine, the University of North Carolina at Chapel Hill, Chapel Hill, NC.
- Lineberger Comprehensive Cancer Center, School of Medicine, the University of North Carolina at Chapel Hill, Chapel Hill, NC.
| | - Chad Deisenroth
- Department of Radiation Oncology, School of Medicine, the University of North Carolina at Chapel Hill, Chapel Hill, NC.
- Lineberger Comprehensive Cancer Center, School of Medicine, the University of North Carolina at Chapel Hill, Chapel Hill, NC.
- Curriculum in Genetics and Molecular Biology, School of Medicine, the University of North Carolina at Chapel Hill, Chapel Hill, NC.
| | - Krishna Bhat
- Departments of Pathology, The University of Texas, M.D. Anderson Cancer Center, Houston, Texas.
| | - Hua Mao
- Department of Pharmacology, School of Medicine, the University of North Carolina at Chapel Hill, Chapel Hill, NC.
| | | | - Yanping Zhang
- Department of Radiation Oncology, School of Medicine, the University of North Carolina at Chapel Hill, Chapel Hill, NC.
- Lineberger Comprehensive Cancer Center, School of Medicine, the University of North Carolina at Chapel Hill, Chapel Hill, NC.
- Department of Pharmacology, School of Medicine, the University of North Carolina at Chapel Hill, Chapel Hill, NC.
- To whom correspondence should be addressed: University of North Carolina at Chapel Hill, Department of Radiation Oncology, Chapel Hill, NC 27599-7512 Tel.: 919-966-7713, Fax.: 919-966-7681,
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Albihn A, Johnsen JI, Henriksson MA. MYC in oncogenesis and as a target for cancer therapies. Adv Cancer Res 2010; 107:163-224. [PMID: 20399964 DOI: 10.1016/s0065-230x(10)07006-5] [Citation(s) in RCA: 186] [Impact Index Per Article: 12.4] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/19/2022]
Abstract
MYC proteins (c-MYC, MYCN, and MYCL) regulate processes involved in many if not all aspects of cell fate. Therefore, it is not surprising that the MYC genes are deregulated in several human neoplasias as a result from genetic and epigenetic alterations. The near "omnipotency" together with the many levels of regulation makes MYC an attractive target for tumor intervention therapy. Here, we summarize some of the current understanding of MYC function and provide an overview of different cancer forms with MYC deregulation. We also describe available treatments and highlight novel approaches in the pursuit for MYC-targeting therapies. These efforts, at different stages of development, constitute a promising platform for novel, more specific treatments with fewer side effects. If successful a MYC-targeting therapy has the potential for tailored treatment of a large number of different tumors.
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Affiliation(s)
- Ami Albihn
- Department of Microbiology, Tumor and Cell Biology, Karolinska Institutet, Stockholm, Sweden
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Regulation of transcription factor function by targeted protein degradation: an overview focusing on p53, c-Myc, and c-Jun. Methods Mol Biol 2010; 647:31-6. [PMID: 20694659 DOI: 10.1007/978-1-60761-738-9_2] [Citation(s) in RCA: 25] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
Regulation of protein degradation is an important mechanism by which concentrations of proteins is controlled in cells. In addition to proteins involved in cell cycle regulation or mitosis, protein levels of many transcription factors are regulated by targeted proteosomal degradation. Regulation of protein degradation and stability is usually linked to post-translational modification of the target protein by phosphorylation. The resulting phosphoaminoacid in the context of the adjacent protein sequence is then recognized by E3 ubiquitin ligase enzymes that covalently attach small ubiquitin protein to the target protein and thereby direct them to be degraded by the proteosomes. Here, we present an overview of mechanisms regulating stability of p53, c-Myc, and c-Jun transcription factors. Especially, the purpose is to highlight the role of protein phosphorylation in the regulation of stability of these transcription factors. We also present examples where phosphorylation can either enhance or inhibit protein degradation. Lastly, we discuss the common theme among p53, c-Myc, and c-Jun proteins that the N-terminal phosphorylation both increases the transactivation capacity of the protein and protects the protein from proteolytic degradation.
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