Article
Biochemistry & Molecular Biology
Xu Dong, Jiabao Xing, Qingchun Liu, Mao Ye, Zhen Zhou, Yantao Li, Rongqin Huang, Zhenhui Li, Qinghua Nie
Summary: In this study, a circRNA-miRNA-mRNA interaction network was identified in chicken primary myoblasts' myogenesis. The circPLXNA2-gga-miR-12207-5P-MDM4 axis was found to play a critical role in regulating myogenesis by inhibiting apoptosis and promoting cell proliferation.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2023)
Review
Oncology
Jin Wu, Guanting Lu, Xinjiang Wang
Summary: MDM4, originally named MDMX, is an oncogene that plays critical roles in promoting cancer cell growth and inhibiting apoptosis by blocking the p53 pathway. Different splicing isoforms of MDM4 show potential therapeutic value in cancer treatment, making them attractive targets for therapy.
AMERICAN JOURNAL OF CANCER RESEARCH
(2021)
Article
Oncology
Vaios Sinatkas, Konstantina Stathopoulou, Ioanna Xagoraris, Jingjing Ye, Dimitra Vyrla, Vasilios Atsaves, Vasiliki Leventaki, L. Jeffrey Medeiros, George Z. Rassidakis, Elias Drakos
Summary: The study revealed that MDMX is highly expressed in ALK+ ALCL and its levels vary in ALK- ALCL. High MDMX levels are more frequently observed in ALK+ ALCL compared to ALK- ALCL. Additionally, inhibition of MDMX is associated with activated p53 signaling, growth inhibition, and apoptotic cell death in wt-p53 ALCL cells.
LEUKEMIA & LYMPHOMA
(2021)
Article
Oncology
Rati Lama, Chao Xu, Samuel L. Galster, Javier Querol-Garcia, Scott Portwood, Cory K. Mavis, Federico M. Ruiz, Diana Martin, Jin Wu, Marianna C. Giorgi, Jill Bargonetti, Eunice S. Wang, Francisco J. Hernandez-Ilizaliturri, Gerald B. Koudelka, Sherry R. Chemler, Ines G. Munoz, Xinjiang Wang
Summary: This study identifies MMRi62 as a novel MDM2-MDM4-targeting agent that can induce apoptosis in leukemia cells, including those with non-functional p53.
FRONTIERS IN ONCOLOGY
(2022)
Article
Medicine, Research & Experimental
Qianru Mei, Zhenhua Yang, Zhengkai Xiang, He Zuo, Zijing Zhou, Xiaochuan Dong, Ludan Zhang, Wenhui Song, Yi Wang, Qinghua Hu, Yong Zhou, Jing Qu
Summary: This study evaluated the efficacy of XI-011, a small molecular inhibitor of MDM4, for treating lung fibrosis. XI-011 significantly reduced MDM4 expression and increased the expression of p53. XI-011 treatment resulted in the resolution of lung fibrosis in mice with no notable impact on normal fibroblast death or the morphology of healthy lungs. Therefore, XI-011 might be a promising therapeutic drug candidate for treating pulmonary fibrosis.
Article
Multidisciplinary Sciences
Haomin Yan, Tsutomu Sasaki, Hideaki Kanki, Yoshiyuki Hirata, Kumiko Nishiyama, Sunao Hisada, Shigenobu Matsumura, Yasuo Nagaoka, Takaaki Sumiyoshi, Seiichi Nagano, Akiko Nakata, Minoru Yoshida, Shinichi Uesato, Hideki Mochizuki
Summary: This study investigated the role of Mdmx in cerebral ischemia and the effects of a small-molecule Protein-Protein Interaction (PPI) inhibitor, K-181, on Mdmx-p53 interactions. The findings revealed that ischemic stroke decreased Mdmx expression and phosphorylation, while Mdmx overexpression showed a neuroprotective effect. The PPI inhibitor, K-181, attenuated neurological deficits by increasing Mdmx expression and selectively inhibiting HDAC6 activity.
SCIENTIFIC REPORTS
(2022)
Article
Biochemistry & Molecular Biology
Rati Lama, Samuel L. Galster, Chao Xu, Luke W. Davison, Sherry R. Chemler, Xinjiang Wang
Summary: MDM2 and MDM4 are validated cancer drug targets for p53-based cancer therapies. In this study, quinolinol derivatives were synthesized and characterized to target the MDM2-MDM4 heterodimer E3 ligase and induce apoptosis in cells. Lead optimization led to the development of compound MMRi71 with improved activity. The compound not only accumulates p53 proteins in wt-p53 bearing cancer cells, but also effectively kills p53-null leukemia cells.
Review
Medicine, General & Internal
Dehua Yu, Zhiyuan Xu, Xiangdong Cheng, Jiangjiang Qin
Summary: miRNAs play a crucial role in regulating the MDMX-p53 network and have significant implications in human cancer. Restoring the activity of p53 by negatively regulating MDMX provides a new approach for cancer treatment.
JOURNAL OF EVIDENCE BASED MEDICINE
(2021)
Article
Biochemistry & Molecular Biology
Viktoria K. Ilic, Olga Egorova, Ernest Tsang, Milena Gatto, Yi Wen, Yong Zhao, Yi Sheng
Summary: The proto-oncogene MDM2 is frequently amplified in many human cancers and its overexpression is associated with poor prognosis. MDM2 shows oncogenic activity by negatively regulating tumor suppressor p53 and proteins involved in DNA repair, cell cycle control, and apoptosis pathways. Inhibition of MDM2 activity has been pursued as an attractive direction for anti-cancer therapeutics. This study identified a biflavonoid compound Hinokiflavone as a promising candidate compound targeting MDM2. Hinokiflavone was shown to bind the MDM2-MDMX RING domain and inhibit MDM2-mediated ubiquitination in vitro. Hinokiflavone treatment downregulated MDM2 and MDMX and induced apoptosis in various cancer cell lines. Hinokiflavone demonstrated tumor-suppressive activity that is both p53-dependent and -independent.
Article
Multidisciplinary Sciences
Francisco J. Sanchez-Rivera, Jeremy Ryan, Yadira M. Soto-Feliciano, Mary Clare Beytagh, Lucius Xuan, David M. Feldser, Michael T. Hemann, Jesse Zamudio, Nadya Dimitrova, Anthony Letai, Tyler Jacks
Summary: The level of mitochondrial apoptotic priming is a critical determinant of cell fate upon p53 reactivation, with cells having high initial priming tending to undergo apoptosis and cells with low priming tending to survive and arrest in the cell cycle. Manipulating the priming levels through BCL-2 or BCL-XL expression or inhibition can affect the outcome of p53 restoration, highlighting mitochondrial apoptotic priming as a key factor in determining cell fate. Moreover, less primed cells can be forced into apoptotic cell fate following p53 activation using p53-independent drugs that increase apoptotic priming.
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
(2021)
Article
Multidisciplinary Sciences
Hudie Wei, Lingzhi Qu, Shuyan Dai, Yun Li, Haolan Wang, Yilu Feng, Xiaojuan Chen, Longying Jiang, Ming Guo, Jun Li, Zhuchu Chen, Lin Chen, Ye Zhang, Yongheng Chen
Summary: The structure of p53/BCL-xL complex reveals the molecular basis of their interaction and provides insight into the mechanisms of p53-mediated mitochondrial apoptosis.
NATURE COMMUNICATIONS
(2021)
Article
Plant Sciences
Chawalit Chatupheeraphat, Sittiruk Roytrakul, Narumon Phaonakrop, Kamolchanok Deesrisak, Sucheewin Krobthong, Usanarat Anurathapan, Dalina Tanyong
Summary: This study identified a novel antileukemic peptide, P2, with high cytotoxicity but minimal effects on normal cells, from Zingiber officinale. P2 in combination with daunorubicin showed enhanced efficacy in decreasing leukemia cell viability, inducing apoptosis and regulating key gene expressions. The upregulation of p53 and downregulation of Bcl-2 by P2 suggest its potential as an alternative drug for leukemia treatment.
Article
Immunology
Senyue Liu, Lin Luo, Fengyuan Zuo, Yi Geng, Yangping Ou, Defang Chen, Shiyong Yang, Wei Luo, Yan Wang, Jun Wang, Xiaoli Huang
Summary: This study revealed the impact of Myxobolus ampullicapsulatus on the gills of goldfish through various methods, identifying the pathological mechanism involving apoptosis and immunosuppression, providing important clues for the prevention and control of Myxoboliosis.
FRONTIERS IN IMMUNOLOGY
(2022)
Article
Medicine, Research & Experimental
Si Chen, Xiang Li, Yinghua Li, Xing Yuan, Chenchen Geng, Songyan Gao, Jinyang Li, Bohan Ma, Zhe Wang, Wuyuan Lu, Hong-Gang Hu
Summary: A stapled peptide-based proteolysis-targeting chimera (SP-PROTAC) was developed, which improved cellular uptake and proteolytic stability while promoting target protein degradation. The optimized SP-PROTAC showed improved binding affinity, helical content, and pharmacokinetic profile compared to its linear counterpart. It effectively killed cancer cells and inhibited tumor progression by promoting the atypical degradation of MDM2 and MDMX and activating p53.
Article
Oncology
Javier Octavio Mejia-Hernandez, Dinesh Raghu, Franco Caramia, Nicholas Clemons, Kenji Fujihara, Thomas Riseborough, Amina Teunisse, Aart G. Jochemsen, Lars Abrahmsen, Giovanni Blandino, Andrea Russo, Cristina Gamell, Stephen B. Fox, Catherine Mitchell, Elena A. Takano, David Byrne, Panimaya Jeffreena Miranda, Reem Saleh, Heather Thorne, Shahneen Sandhu, Scott G. Williams, Simon P. Keam, Ygal Haupt, Sue Haupt
Summary: Prostate cancer is a common male cancer, and high levels of MDM4 are associated with an increased risk of prostate cancer. Inhibiting MDM4 may serve as a novel treatment approach for prostate cancer.
Article
Engineering, Biomedical
Fabio Maiullari, Maila Chirivi, Marco Costantini, Anna Maria Ferretti, Sandro Recchia, Silvia Maiullari, Marika Milan, Dario Presutti, Valentina Pace, Marcello Raspa, Ferdinando Scavizzi, Massimo Massetti, Lella Petrella, Mara Fanelli, Marta Rizzi, Orazio Fortunato, Fabiola Moretti, Eugenio Caradonna, Claudia Bearzi, Roberto Rizzi
Summary: Extracellular vesicles have shown to be effective in mediating intercellular communication, and recent studies have demonstrated the use of EVs in combination with 3D bioprinting to promote angiogenesis in regenerative medicine.
Article
Oncology
Micol Di Segni, Ilaria Virdia, Alessandra Verdina, Carla Azzurra Amoreo, Silvia Baldari, Gabriele Toietta, Maria Grazia Diodoro, Marcella Mottolese, Isabella Sperduti, Fabiola Moretti, Simonetta Buglioni, Silvia Soddu, Giuliana Di Rocco
Summary: This study investigated the expression of HIPK2 in colorectal cancer and its association with disease progression and mutational patterns. The results showed that the percentage of HIPK2-positive cells increased with tumor progression and was significantly correlated with tumor-stage and poorer prognosis. Additionally, high HIPK2 expression was found to be significantly associated with KRAS mutations but not with other cancer-related genes. Functional analysis revealed that activation of the RAS pathway, either through KRAS mutation or upstream receptor stimulation, increased HIPK2 expression. Depletion of HIPK2 impaired ERK phosphorylation and tumor growth in colorectal cancer cells with KRAS mutations.
MOLECULAR CANCER RESEARCH
(2022)
Article
Oncology
Emmanuel de Billy, Marsha Pellegrino, Domenico Orlando, Giulia Pericoli, Roberta Ferretti, Pietro Businaro, Maria Antonietta Ajmone-Cat, Sabrina Rossi, Lucia Lisa Petrilli, Nicola Maestro, Francesca Diomedi-Camassei, Marco Pezzullo, Cristiano De Stefanis, Paola Bencivenga, Alessia Palma, Rossella Rota, Francesca Del Bufalo, Luca Massimi, Gerrit Weber, Chris Jones, Andrea Carai, Simona Caruso, Biagio De Angelis, Ignazio Caruana, Concetta Quintarelli, Angela Mastronuzzi, Franco Locatelli, Maria Vinci
Summary: This study investigated the anti-tumor activity of GD2-CAR T-cells in treating DMG/DIPG and identified the potential of using IGF1R/IR inhibitors in combination with GD2-CAR T-cells. The results showed that the dual IGF1R/IR antagonists BMS-754807 and linsitinib were able to inhibit tumor cell viability without affecting CAR T-cells. Linsitinib also improved the function of GD2-CAR T-cells. The combination of linsitinib and GD2-CAR T-cells demonstrated enhanced anti-tumor activity in vitro, ex vivo, and in vivo models of DIPG.
Article
Biochemistry & Molecular Biology
Silvia Middei, Ludovica Giorgini, Valentina Vacca, Francesca Storri, Sabrina Putti, Georgios Strimpakos, Marcello Raspa, Ferdinando Scavizzi, Fabiola Moretti, Francesca R. D'Amato
Summary: Epidemiological evidence suggests that stress and aversive psychological conditions can influence cancer progression, while well-being can provide protection. This study used mice to demonstrate that being raised in a positive psychological environment can confer protection against tumor development. The involvement of p53 and p21 proteins may play a role in this protective effect.
Review
Oncology
Giulia Marelli, Nicolo Morina, Federica Portale, Marta Pandini, Marta Iovino, Giusy Di Conza, Ping-Chih Ho, Diletta Di Mitri
Summary: Macrophages are key players in the immune system and their dysfunction can contribute to various diseases, including cancer. Lipid metabolism plays a role in macrophage activation and lipid accumulation can lead to pathogenic features. A subset of lipid-loaded macrophages, known as tumor-associated macrophages (TAMs), are involved in tumor growth and immune suppression.
JOURNAL FOR IMMUNOTHERAPY OF CANCER
(2022)
Article
Biochemistry & Molecular Biology
Ingrid Cifola, Federica Fratini, Beatrice Cardinali, Valentina Palmieri, Giuliana Gatti, Tommaso Selmi, Sara Donzelli, Andrea Sacconi, Valeriana Cesarini, Hany E. Marei, Massimilano Papi, Giovanni Blandino, Carlo Cenciarelli, Germana Falcone, Igea D'Agnano
Summary: Glioblastoma (GBM) is a common and aggressive brain tumor with limited treatment options. The heterogeneity of GBM tumor cells, especially the cancer stem cells (CSCs), plays a crucial role in clinical outcomes. This study explored the role of extracellular vesicles (EVs) in CSCs and GBM tumor cells, finding that the miRNA and protein content of EVs differ, with GBM-sEVs enriched for tumor suppressor miRNAs and oncoproteins, and CSC-sEVs enriched for pro-tumor miRNAs and proteins related to sternness, cell proliferation, and apoptosis.
Article
Biochemistry & Molecular Biology
Emanuela Teveroni, Fiorella Di Nicuolo, Edoardo Vergani, Carmine Bruno, Giuseppe Maulucci, Giada Bianchetti, Anna Laura Astorri, Giuseppe Grande, Jacopo Gervasoni, Lavinia Santucci, Marco De Spirito, Andrea Urbani, Alfredo Pontecorvi, Francesca Mancini, Domenico Milardi
Summary: The study demonstrates the activation of sperm cells through the olfactory receptor 51E2 (OR51E2) upon stimulation with volatile short-chain fatty acids (SCFAs). SCFAs promote sperm migration and a more linear sperm-cell orientation. The study also reveals the ability of cervical mucus to directly activate sperm cells. These findings provide insights into the role of chemosensory receptors in reproductive activity and offer potential strategies for the treatment of infertility.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2022)
Article
Oncology
Emanuela Teveroni, Fiorella Di Nicuolo, Edoardo Vergani, Giada Bianchetti, Carmine Bruno, Giuseppe Maulucci, Marco De Spirito, Tonia Cenci, Francesco Pierconti, Gaetano Gulino, Pierfrancesco Bassi, Alfredo Pontecorvi, Domenico Milardi, Francesca Mancini
Summary: This study investigated the role of PTTG1 in the EMT process in seminoma. The results showed that PTTG1 transcriptionally represses E-Cadherin through its cooperation with the transcriptional repressor ZEB1. It also demonstrated that PTTG1 and ZEB1 strongly localize together in the periphery of the tumors. These findings suggest that PTTG1 is a prognostic factor in seminoma clinical management.
Article
Cell Biology
Juan Fernandez-Garcia, Fabien Franco, Sweta Parik, Patricia Altea-Manzano, Antonino Alejandro Pane, Dorien Broekaert, Joke van Elsen, Ines Vermeire, Tessa Schalley, Melanie Planque, Thomas van Brussel, Rogier Schepers, Elodie Modave, Tobias K. Karakach, Peter Carmeliet, Diether Lambrechts, Ping-Chih Ho, Sarah-Maria Fendt
Summary: The metabolism of T cells undergoes dynamic changes during immune response. Researchers used single-cell RNA sequencing to study the metabolic dynamics of CD8(+) T cells activated and differentiated in vitro. They found that activated T cells have differential reliance on the synthesis and uptake of non-essential amino acids. The expression dynamics of the metabolic gene asparagine synthetase (Asns) was identified as a modulator of CD8(+) T cell differentiation.
Article
Biochemistry & Molecular Biology
Carmela Serpe, Antonio Michelucci, Lucia Monaco, Arianna Rinaldi, Mariassunta De Luca, Pietro Familiari, Michela Relucenti, Erika Di Pietro, Maria Amalia Di Castro, Igea D'Agnano, Luigi Catacuzzeno, Cristina Limatola, Myriam Catalano
Summary: All cells are capable of secreting extracellular vesicles (EVs), which play a role in intercellular communication. In brain tumors, EVs facilitate bidirectional crosstalk between glioblastoma cells and healthy cells, particularly astrocytes. This study demonstrates that astrocyte-derived small EVs (sEVs) have a defensive mechanism against tumor cell growth and invasion, mediated by the transfer of factors that hinder glioma growth.
Article
Biochemistry & Molecular Biology
Giulia Cappelli, Daniela Giovannini, Laura Vilardo, Annalisa Basso, Ilaria Iannetti, Marianna Massa, Giuseppe Ruberto, Ryan Muir, Carlo Pastore, Igea D'Agnano, Francesca Mariani
Summary: Given the pro-oxidant status of tumour cells, the combination of anti- and pro-oxidant substances can enhance the cytotoxicity of anti-tumour drugs. In this study, the effect of C. zeylanicum essential oil (CINN-EO) on a human metastatic melanoma cell line (M14) was assessed. CINN-EO inhibited cell growth, disrupted cell cycle, increased ROS and Fe(II) levels, and depolarized mitochondrial membrane. It also affected iron metabolism and stress response gene expression. The induction of incomplete stress response specific to cancer cells by CINN-EO can inhibit melanoma cell proliferation and enhance drug cytotoxicity.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2023)
Article
Oncology
Matteo Centonze, Giusy Di Conza, Michael Lahn, Isabel Fabregat, Francesco Dituri, Isabella Gigante, Grazia Serino, Rosanna Scialpi, Livianna Carrieri, Roberto Negro, Elena Pizzuto, Gianluigi Giannelli
Summary: The study showed that IOA-289 can inhibit the growth and migration of gastrointestinal tract tumor cell lines, especially in FBS-free culture medium. In addition, IOA-289 can induce apoptosis in gastrointestinal tract tumor cells and increase the expression of pro-apoptotic proteins.
JOURNAL OF EXPERIMENTAL & CLINICAL CANCER RESEARCH
(2023)
Article
Oncology
Zoe Johnson, Chiara Tarantelli, Elisa Civanelli, Luciano Cascione, Filippo Spriano, Amy Fraser, Pritom Shah, Tyzoon Nomanbhoy, Sara Napoli, Andrea Rinaldi, Karolina Niewola-Staszkowska, Michael Lahn, Dominique Perrin, Mathias Wenes, Denis Migliorini, Francesco Bertoni, Lars van der Veen, Giusy Di Conza
Summary: IOA-244, a first-in-class non-ATP-competitive PI3K & delta; inhibitor, has shown potential anticancer activity in solid tumors by modulating T-cell responses and direct antitumor effects. It inhibits regulatory T-cell proliferation and promotes infiltration of CD8 and natural killer cells, reshaping the balance of tumor-infiltrating cells. These findings support the ongoing clinical trials of IOA-244 in patients with solid tumors and hematologic cancers.
CANCER RESEARCH COMMUNICATIONS
(2023)
Review
Immunology
Giusy Di Conza, Ping-Chih Ho, Juan R. Cubillos-Ruiz, Stanley Ching-Cheng Huang
Summary: Initiating and maintaining optimal immune responses requires the endoplasmic reticulum's orchestration of protein synthesis and processing in leukocytes. Dysregulation of the unfolded protein response (UPR) in immune cells can lead to various pathologies. This review explores the role of UPR in immune cells and discusses how modulating this pathway could be used therapeutically.
NATURE REVIEWS IMMUNOLOGY
(2023)
Review
Oncology
Hany E. Marei, Asmaa Althani, Nahla Afifi, Anwarul Hasan, Thomas Caceci, Ingrid Cifola, Sara Caratelli, Giuseppe Sconocchia, Igea D'Agnano, Carlo Cenciarelli
Summary: EVs have a diverse range of molecules and play a crucial role in the development of tumors, particularly in gliomas. Current research is uncovering the potential utility of EVs in the diagnosis, prognosis, and treatment of glioblastoma.