Article
Multidisciplinary Sciences
Shota Shimizu, Kazuaki Yoshioka, Sho Aki, Yoh Takuwa
Summary: PI3K-C2 alpha is essential for clathrin-mediated endocytosis of the gamma-secretase complex, facilitating the cleavage of endocytosed Notch1 by the gamma-secretase complex to generate NICD1 in ECs.
SCIENTIFIC REPORTS
(2021)
Review
Biochemistry & Molecular Biology
Philipp Alexander Koch, Gillian Leigh Dornan, Manuel Hessenberger, Volker Haucke
Summary: The phosphoinositide 3-kinase (PI3K) family plays crucial roles in cell signaling and membrane trafficking by producing 3-phosphorylated phosphoinositides. While class I and class III PI3Ks have been extensively studied, class II enzymes remain relatively understudied. Recent research has started uncovering their roles in development, endocytosis, signal transduction, and cell migration, but the mechanisms controlling their localization and enzymatic activity are still largely unknown.
Article
Pharmacology & Pharmacy
Ava Safaroghli-Azar, Mohammad-Javad Sanaei, Atieh Pourbagheri-Sigaroodi, Davood Bashash
Summary: Lipid signaling refers to the biological process in which a lipid messenger binds to a protein target, converting its effects to specific cellular responses. The family of phosphoinositide 3-kinase (PI3K) plays a crucial role in this pathway, affecting various aspects of cellular biology such as cell survival, proliferation, migration, endocytosis, intracellular trafficking, metabolism, and autophagy. Different classes of PI3Ks have been identified in yeast and mammals, with class I PI3Ks being extensively studied in cancer biology. Abnormal activation of class I PI3Ks has been implicated in human tumors, particularly through activating mutations in the PIK3CA gene. Class II and III PI3Ks are involved in regulating vesicle trafficking and autophagy processes. This review aims to discuss the latest research findings on PI3Ks-mediated cell biological processes and explore the mechanisms by which different types of phosphoinositides derived from PI3Ks act.
EUROPEAN JOURNAL OF PHARMACOLOGY
(2023)
Article
Genetics & Heredity
Kerong Chen, Zhiling Yan, Xudong Dong, Yan Liang, Yueting Yao, Shao Zhang, Weipeng Liu, Chuanyin Li, Yufeng Yao, Li Shi
Summary: Polymorphisms in miRNA genes (rs107822 in miR-219a and rs2292832 in miR-149) are associated with cervical cancer risk, but not with cervical intraepithelial neoplasia.
FRONTIERS IN GENETICS
(2022)
Article
Medicine, Research & Experimental
Hasibur Rehman, Darshan S. Chandrashekar, Chakravarthi Balabhadrapatruni, Saroj Nepal, Sai Akshaya Hodigere Balasubramanya, Abigail K. Shelton, Kasey R. Skinner, Ai-Hong Ma, Ting Rao, Sumit Agarwal, Marie-Lisa Eich, Alyncia D. Robinson, Gurudatta Naik, Upender Manne, George J. Netto, C. Ryan Miller, Chong-Xian Pan, Guru Sonpavde, Sooryanarayana Varambally, James E. Ferguson
Summary: The study reveals that bladder cancers with ARID1A mutations are more sensitive to EZH2 inhibitors and/or PI3K inhibitors. Mechanistic studies demonstrate that ARID1A deficiency leads to a dependency on PI3K signaling, and EZH2 inhibitor sensitivity is associated with upregulation of PIK3IP1. Moreover, combination therapy with EZH2 and PI3K inhibitors shows a synergistic effect on ARID1A-deficient bladder cancer.
Article
Biochemistry & Molecular Biology
Chengbin Yang, Menghui Wang, Yimin Gong, Mingli Deng, Yun Ling, Qingquan Li, Jianxin Wang, Yaming Zhou
Summary: A novel PI3K inhibitor, FD2056, was discovered using 7-azaindole-based fragment-oriented growth. FD2056 demonstrated potent inhibitory activity against PI3K and enhanced CDK2 inhibition, as well as moderate selectivity among 108 kinases. In cellular assays, FD2056 showed superior anti-proliferative profiles against TNBC cells and increased apoptosis of MDA-MB-231 cells in a dose-dependent manner. FD2056 also exhibited more efficacious anti-TNBC activity than the reference drugs BKM120 and CYC202 in the MDA-MB-231 xenograft model. These findings suggest that FD2056 has potential as a promising anticancer compound and co-targeting PI3K and CDK2 pathways may be a viable therapeutic strategy for TNBC.
BIOORGANIC CHEMISTRY
(2023)
Article
Biochemistry & Molecular Biology
Alexandra M. Simond, Tung Bui, Dongmei Zuo, Virginie Sanguin-Gendreau, Trisha Rao, Wayne A. Phillips, Robert D. Cardiff, William J. Muller
Summary: This study found that the p110 alpha(HR) mutation attenuates metastatic behavior and is associated with the formation of ductal carcinoma in situ (DCIS) in ErbB2-driven breast cancer.
Article
Oncology
Peter Savas, Louisa L. Lo, Stephen J. Luen, Elizabeth F. Blackley, Jason Callahan, Kate Moodie, Courtney T. van Geelen, Yi-An Ko, Chen -Fang Weng, Lironne Wein, Maria Joao Silva, Andjelija Zivanovic Bujak, Miriam M. Yeung, Sarah Ftouni, Rodney J. Hicks, Prudence A. Francis, Chee Khoon Lee, Sarah -Jane Dawson, Sherene Loi
Summary: Alpelisib monotherapy demonstrated efficacy in heavily pretreated ER + breast cancer, and the dynamics of PIK3CA mutation and ESR1 mutation detected in plasma can serve as candidate biomarkers for predicting treatment response.
Article
Plant Sciences
Xiao-chen Li, Shuai Wang, Xin-xin Yang, Tian-jiao Li, Jia-xing Gu, Lin Zhao, Yong-rui Bao, Xian-sheng Meng
Summary: This study aimed to investigate the treatment of colorectal cancer (CRC) using Patrinia villosa Juss. (P.V) and clarify its underlying mechanism. The results from animal models showed that P.V can reduce tumor number and diameter, improve colon cell injury, and decrease levels of CRC biomarkers. Metabolomics analysis revealed changes in endogenous metabolites, indicating that P.V modulates the glycerol phospholipid metabolites closely related to the PI3K target and PI3K/Akt signaling pathway for CRC treatment.
JOURNAL OF ETHNOPHARMACOLOGY
(2023)
Article
Biochemistry & Molecular Biology
Nurul Nadirah Razali, Raja Affendi Raja Ali, Khairul Najmi Muhammad Nawawi, Azyani Yahaya, Norfilza M. Mokhtar
Summary: This study identified somatic variants in cytokine-induced PI3K-related genes in ulcerative colitis (UC), colorectal cancer (CRC), and colitis-associated cancer (CAC). The results showed changes in levels of IL23R, IL12Rss1, IL12Rss2, TYK2, JAK2, and OSMR, with the IL23R variant rs10889677 potentially linking CAC, UC, and CRC. Further functional research on these variants is recommended to gain insight into the relationship between inflammation and cancer risk in the PI3K pathway.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2022)
Article
Medicine, Research & Experimental
Lena Hoelzen, Jan Mitschke, Claudia Schoenichen, Maria Elena Hess, Sophia Ehrenfeld, Melanie Boerries, Cornelius Miething, Tilman Brummer, Thomas Reinheckel
Summary: This study suggests that proteases can act synergistically with PI3K inhibition in breast cancer cells, leading to enhanced therapeutic outcomes. Through a series of experiments, the researchers identified Usp7, Metap1, and Metap2 as key proteases that exhibit synthetic lethal effects when combined with PI3K inhibitors.
Article
Biochemistry & Molecular Biology
Chengbin Yang, Mingzhu Lu, Yi Chen, Ruiqing Xiang, Tianze Qiu, Yu Jia, Yongtai Yang, Xiaofeng Liu, Mingli Deng, Yun Ling, Yaming Zhou
Summary: Breast cancer is the cancer with the highest incidence globally, and the newly designed 7-azaindole derivatives FD2054 and FD2078 are potent PI3K inhibitors with promising antiproliferative activity against MCF-7 and MDA-MB-231 breast cancer cell lines, showing potential as candidates for anticancer drug development.
BIOORGANIC CHEMISTRY
(2021)
Review
Pharmacology & Pharmacy
Ayda Baghery Saghchy Khorasani, Atieh Pourbagheri-Sigaroodi, Ali Pirsalehi, Ava Safaroghli-azar, Mohammad Reza Zali, Davood Bashash
Summary: Genetic and epigenetic alterations have long been the focus of cancer pathogenesis research, with dysregulated genes and protein products potentially affecting cancer cell growth through signaling cascades regulating cell survival and metabolism. The activation of the phosphatidylinositol-3-kinase (PI3K) axis in about one-third of human cancers, including gastric cancer, plays a significant role in the development of malignancies. This indicates the potential importance of targeting this axis in therapeutic strategies for such cancers.
EUROPEAN JOURNAL OF PHARMACOLOGY
(2021)
Article
Oncology
Eun Jung Sohn
Summary: Ovarian cancer is one of the most lethal gynecologic diseases and commonly diagnosed cancer among women worldwide. This study found that P13K plays an important regulatory role in ovarian cancer development, and PIK3R3 serves as a potential predictive marker for therapeutic effectiveness and a candidate for developing novel therapeutic approaches.
Article
Cell Biology
Chantal Alkhoury, Nathaniel F. Henneman, Volodymyr Petrenko, Yui Shibayama, Arianna Segaloni, Alexis Gadault, Ivan Nemazanyy, Edouard Le Guillou, Amare Desalegn Wolide, Konstantina Antoniadou, Xin Tong, Teruya Tamaru, Takeaki Ozawa, Muriel Girard, Karim Hnia, Dominik Lutter, Charna Dibner, Ganna Panasyuk
Summary: The class 3 phosphatidylinositol-3-kinase Vps15 subunit plays a crucial role in transcriptional gene regulation and metabolic rhythmicity. It interacts with RNA polymerase II and co-localizes with active transcription sites. Loss of Vps15 leads to decreased transcriptional activity of Bmal1-Clock, indicating its non-redundancy with the Vps34 subunit. Additionally, Vps15 is required for metabolic rhythmicity in liver and promotes pro-anabolic de novo purine synthesis.
NATURE CELL BIOLOGY
(2023)
Review
Neurosciences
Mara Brancaccio, Flora Pirozzi, Emilio Hirsch, Alessandra Ghigo
JOURNAL OF PHYSIOLOGY-LONDON
(2020)
Review
Oncology
Luca Gozzelino, Maria Chiara De Santis, Federico Gulluni, Emilio Hirsch, Miriam Martini
FRONTIERS IN ONCOLOGY
(2020)
Article
Microbiology
Sara Petrillo, Giovanna Carra, Paolo Bottino, Elisa Zanotto, Maria Chiara De Santis, Jean Piero Margaria, Alessandro Giorgio, Giorgia Mandili, Miriam Martini, Rossana Cavallo, Davide Barberio, Fiorella Altruda
Article
Oncology
Stefanie Herda, Andreas Heimann, Benedikt Obermayer, Elisa Ciraolo, Stefanie Althoff, Josefine Russ, Corinna Grunert, Antonia Busse, Lars Bullinger, Antonio Pezzutto, Thomas Blankenstein, Dieter Beule, Il-Kang Na
Summary: Extended in vitro expansion of T cells can enhance T cell yield and functionality, providing a practicable alternative for patients with insufficient T cells after standard manufacturing process. This approach has shown positive results in both murine and human T cells, increasing accessibility to adoptive T cell therapy for patients in need.
INTERNATIONAL JOURNAL OF CANCER
(2021)
Article
Biochemistry & Molecular Biology
Francesca Grisan, Martina Spacci, Carlotta Paoli, Andrea Costamagna, Marco Fantuz, Miriam Martini, Konstantinos Lefkimmiatis, Alessandro Carrer
Summary: This study demonstrates the impact of cholesterol on the plasticity of normal pancreatic acinar cells and the cyclic AMP/PKA axis. Cholesterol supplementation enhances ductal transdifferentiation in isolated primary wild-type acinar cells, associated with cAMP signaling. The ability of cholesterol to activate cAMP signaling is lost in tumor cells.
Article
Urology & Nephrology
Federica Barutta, Shunsuke Kimura, Koji Hase, Stefania Bellini, Beatrice Corbetta, Alessandro Corbelli, Fabio Fiordaliso, Antonella Barreca, Mauro Giulio Papotti, Gian Marco Ghiggeri, Gennaro Salvidio, Dario Roccatello, Valentina Audrito, Silvia Deaglio, Roberto Gambino, Stefania Bruno, Giovanni Camussi, Miriam Martini, Emilio Hirsch, Marilena Durazzo, Hiroshi Ohno, Gabriella Gruden
Summary: The study found that the M-Sec?TNT system plays an important protective role in podocytes by rescuing them via mitochondrial horizontal transfer. Overexpression of M-Sec in FSGS suggests a cytoprotective role, while M-Sec deletion leads to progressive FSGS development. These findings provide insight into potential therapeutic targets for FSGS and suggest regenerative cell-based therapy options through TNT-mediated organelle transfer.
JOURNAL OF THE AMERICAN SOCIETY OF NEPHROLOGY
(2021)
Editorial Material
Gastroenterology & Hepatology
Raffaella Casolino, Andrew V. Biankin
Review
Oncology
Huayi Li, Lorenzo Prever, Emilio Hirsch, Federico Gulluni
Summary: The PI3K signaling pathway is crucial in breast cancer and inhibitors targeting this pathway show promising activity, but resistance and adverse reactions limit their efficacy. Combination therapies and identifying suitable patient subpopulations are needed to enhance therapeutic benefit.
Article
Biology
Paulin Brosinsky, Julia Bornbaum, Bjorn Warga, Lisa Schulz, Klaus-Dieter Schluter, Alessandra Ghigo, Emilio Hirsch, Rainer Schulz, Gerhild Euler, Jacqueline Heger
Summary: The study demonstrates the involvement of PI3K and ALK5/SMAD pathways in TGF beta(1)-induced cardiomyocyte apoptosis and impaired function, with a partial dependence on PI3K gamma.
Article
Gastroenterology & Hepatology
Andrea Costamagna, Dora Natalini, Maria del Pilar Camacho Leal, Matilde Simoni, Luca Gozzelino, Paola Cappello, Francesco Novelli, Chiara Ambrogio, Paola Defilippi, Emilia Turco, Elisa Giovannetti, Emilio Hirsch, Sara Cabodi, Miriam Martini
Summary: High expression of p130Cas is associated with higher histologic grade and poor prognosis in PDAC. Deletion of p130Cas inhibits acinar-derived tumorigenesis and progression by suppressing PI3K-AKT signaling. Targeting the PI3K pathway may be a rational therapeutic strategy for tumors with high expression of p130Cas.
Article
Multidisciplinary Sciences
Federico Gulluni, Lorenzo Prever, Huayi Li, Petra Krafcikova, Ilaria Corrado, Wen-Ting Lo, Jean Piero Margaria, Anlu Chen, Maria Chiara De Santis, Sophie J. Cnudde, Joseph Fogerty, Alex Yuan, Alberto Massarotti, Nasrin Torabi Sarijalo, Oscar Vadas, Roger L. Williams, Marcus Thelen, David R. Powell, Markus Schueler, Michael S. Wiesener, Tamas Balla, Hagit N. Baris, Dov Tiosano, Brian M. McDermott, Brian D. Perkins, Alessandra Ghigo, Miriam Martini, Volker Haucke, Evzen Boura, Giorgio Roberto Merlo, David A. Buchner, Emilio Hirsch
Summary: The cytokinetic process in the lens, which depends on PI3K-C2alpha, PI(3,4)P-2, and VPS36, is essential for preventing premature senescence and cataract. Loss of these components impairs cytokinesis and leads to cell damage, triggering senescence in the lens of fish, mice, and humans.
Review
Biochemistry & Molecular Biology
Jean Piero Margaria, Lucia Moretta, Jose Carlos Alves-Filho, Emilio Hirsch
Summary: This article summarizes the progress in understanding the role of PI3K/Akt in the development of lung fibrosis and its causative pathological context, including sepsis as well as acute lung injury (ALI) and its consequent acute respiratory distress syndrome (ARDS). Current knowledge about PI3K inhibitors for pulmonary fibrosis treatment, including drugs under development as well as in clinical trials, is further summarized. The discussion also includes how the design of inhaled compounds targeting the PI3K pathways might potentiate efficacy and improve tolerability.
Editorial Material
Cardiac & Cardiovascular Systems
Carlo G. Tocchetti, Alessandra Ghigo, Emilio Hirsch
Summary: This editorial discusses the study conducted by Lu et al. on the protective effect of circular RNA derived from the insulin receptor locus against doxorubicin-induced cardiotoxicity.
EUROPEAN HEART JOURNAL
(2022)
