Article
Immunology
Jihua Tian, Sijia Chang, He Ji, Taiping Huang, Haixiu Guo, Jing Kang, Yanhong Wang, Yun Zhou
Summary: This study demonstrated that rapamycin can reduce mesangial cell proliferation and arrest the cell cycle in the G1 phase, with higher concentrations showing more significant inhibition of p70S6K phosphorylation. Furthermore, it revealed that high-dose rapamycin leads to ERK1/2 activation through a p70S6K/PI3K/MAPK feedback loop in rat MCs, reducing the inhibitory effect on MC proliferation.
INTERNATIONAL JOURNAL OF IMMUNOPATHOLOGY AND PHARMACOLOGY
(2021)
Article
Biochemistry & Molecular Biology
Gwen R. Buel, Huy Q. Dang, John M. Asara, John Blenis, Anders P. Mutvei
Summary: This study found that prolonged deprivation of arginine and/or leucine leads to reactivation of mTORC1 activity, reaching activation levels similar to those observed in nutrient-rich conditions. Surprisingly, this reactivation is independent of amino acid regeneration, but dependent on PI3K/Akt signaling. These findings expand our understanding of the role of mTORC1 in growth-related diseases and suggest that dietary intervention by removing leucine and/or arginine may be an ineffective therapeutic approach.
JOURNAL OF BIOLOGICAL CHEMISTRY
(2022)
Article
Multidisciplinary Sciences
Michael J. Wagner, Yasmin A. Lyons, Jean H. Siedel, Robert Dood, Archana S. Nagaraja, Monika Haemmerle, Lingegowda S. Mangala, Pritha Chanana, Alexander J. Lazar, Wei-Lien Wang, Vinod Ravi, Eric C. Holland, Anil K. Sood
Summary: Angiosarcoma is an aggressive malignancy with high mortality rate, showing active MAPK signaling pathway and response to MEK inhibitor trametinib. Combined inhibition of VEGF and MAPK pathways with cediranib and trametinib has additive effects in vitro and synergistic effects in vivo, leading to smaller tumors compared to single agent treatments. RNA-seq demonstrates distinct expression signatures between trametinib and combined treatment, supporting the potential of combined VEGFR and MEK inhibition in clinical studies for angiosarcoma.
SCIENTIFIC REPORTS
(2021)
Article
Environmental Sciences
Yan Jiang, Xiahao Zhao, Jin Chen, Stanley Aniagu, Tao Chen
Summary: Growing evidence suggests a link between maternal exposure to PM2.5 and congenital heart diseases in offspring. In this study, researchers found that suppressing the PI3K/akt signaling pathway protected zebrafish larvae from cardiac defects caused by EOM from PM2.5. Akt2 activation was identified as a key mechanism for EOM-induced heart malformations. Additionally, EOM-induced akt2 overactivation increased ROS production, decreased mitochondrial membrane potential, and triggered intrinsic apoptosis in zebrafish embryos.
ENVIRONMENTAL POLLUTION
(2023)
Article
Biochemistry & Molecular Biology
Sanam Sane, Rekha Srinivasan, Rashaun A. A. Potts, Morgan Eikanger, Diana Zagirova, Jessica Freeling, Casey A. A. Reihe, Ryan M. M. Antony, Brij K. K. Gupta, Douglas Lynch, Jonathan Bleeker, Hassan Turaihi, Angela Pillatzki, Wei Zhou, Xu Luo, Michael Linnebacher, Diing Agany, Etienne Gnimpieba Zohim, Lisa E. E. Humphrey, Adrian R. R. Black, Khosrow Rezvani
Summary: The mTORC2 pathway promotes tumor progression in colorectal cancer (CRC). UBXN2A is identified as a tumor suppressor protein that inhibits the mTORC2 pathway. UBXN2A reduces AKT phosphorylation, which is crucial for cell migration, downstream of mTORC2. UBXN2A targets Rictor protein for degradation, leading to inhibition of mTORC2 pathway and regulation of various cellular processes in CRC.
Article
Biochemistry & Molecular Biology
Bence Hajdu, Marianna Holczer, Gergely Horvath, Gabor Szederkenyi, Orsolya Kapuy
Summary: The regulation of autophagy involves complex interactions between mTORC1, ULK1, and PP2A. In this study, the authors investigate the role of double-negative and positive feedback loops in the decision-making process between autophagy and non-autophagy states. Through molecular biological experiments and theoretical analysis, they confirm that active ULK1 can up-regulate PP2A when mTORC1 is inhibited. They also explain the importance of cellular PP2A level in stress response mechanism. This research provides insights into the molecular balance of ULK1-mTORC1-PP2A in autophagy and its relevance in cellular stress-related diseases.
Article
Cell Biology
Xiaolin Pei, Fangxu Zheng, Yin Li, Zhoujun Lin, Xiao Han, Ya Feng, Zhenhuan Tian, Dunqiang Ren, Ke Cao, Chenggang Li
Summary: Idiopathic pulmonary fibrosis (IPF) is a serious disease that leads to respiratory failure and early mortality. This study found that Niclosamide ethanolamine salt (NEN) could significantly improve lung function and reduce fibrosis in an IPF animal model. The results also showed that NEN inhibits abnormal fibroblast proliferation and excessive extracellular matrix production through the regulation of the PI3K-mTORC1 and autophagy pathways. These findings provide strong evidence for the potential therapeutic role of NEN in IPF.
Article
Multidisciplinary Sciences
Chih-Yao Chung, Kritarth Singh, Vassilios N. Kotiadis, Gabriel E. Valdebenito, Jee Hwan Ahn, Emilie Topley, Joycelyn Tan, William D. Andrews, Benoit Bilanges, Robert D. S. Pitceathly, Gyorgy Szabadkai, Mariia Yuneva, Michael R. Duchen
Summary: Heteroplasmic mtDNA mutations, specifically the m.3243 A > G mutation, lead to activated PI3K-Akt-mTORC1 pathway in cells, and inhibiting this pathway reduces mutant mtDNA load. Pharmacological inhibition of PI3K, Akt, or mTORC1 can potentially benefit people with the consequences of the m.3243 A > G mutation by reducing mutant mtDNA load and improving cellular bioenergetic function.
NATURE COMMUNICATIONS
(2021)
Article
Oncology
Lauren Dennison, Amanda Ruggieri, Aditya Mohan, James Leatherman, Kayla Cruz, Skylar Woolman, Nilofer Azad, Gregory B. Lesinski, Elizabeth M. Jaffee, Mark Yarchoan
Summary: MEKi has potential in enhancing antitumor immunity but its effects vary depending on the context; MEKi affects both tumor cells and T cells, but also impairs T cell activation in the tumor microenvironment; T cell agonist therapy can maximize the effects of MEKi on the antitumor immune response.
CANCER IMMUNOLOGY RESEARCH
(2021)
Article
Geriatrics & Gerontology
H. G. Keizer, R. Brands, W. Seinen
Summary: The purpose of this article is to investigate the role of the AMP-kinase pathway in the induction of health benefits by exercise, drugs, and health ingredients, and its relation to ageing. It is challenging to understand how the activation of a single biochemical pathway can produce various concurrent health benefits. The AMP-kinase pathway functions as an integrated stress response system with a feedback loop, detecting changes in ratios and toxins, and activating a protective response to promote longevity. Inactivation of the AMP-kinase pathway with age explains the negative impact on health benefits. The presence of a feedback loop positions this pathway as an AMPK-dependent integrated stress response system.
Article
Cell Biology
Rui Lin, Xunxia Bao, Hui Wang, Sibo Zhu, Zhongyan Liu, Quanning Chen, Kaixing Ai, Baomin Shi
Summary: The mechanism of TRPM2 in pancreatic cancer involves the activation of PKC/MAPK pathways, leading to enhanced proliferation, migration, and invasion abilities of PA cells. TRPM2 is negatively correlated with overall survival and progression-free survival time in PA patients, while its expression increases with tumor stage. Inhibitors of PKC/MEK significantly inhibit PA cell growth, suggesting a potential therapeutic target for pancreatic cancer.
CELL DEATH & DISEASE
(2021)
Article
Multidisciplinary Sciences
Sa Gong, Chang Li, Qingyang Leng, Chongxiao Liu, Yi Zhu, Hongli Zhang, Xiaohua Li
Summary: This study found that mTORC1 inhibitor can improve adipose fibrosis by suppressing fibrosis-related gene expression in hypoxia and TGF-beta-induced fibrotic preadipocytes.
Article
Oncology
Cong Xu, Yi-Ming Li, Bo Sun, Fang-Jing Zhong, Lian-Yue Yang
Summary: This study revealed that decreased expression of GNA14 was associated with aggressive features in hepatocellular carcinoma (HCC), while high expression was linked to better overall and disease-free survival. GNA14 acted as a suppressor inhibiting liver cancer progression through MAPK/JNK and PI3K/AKT signaling pathways.
Article
Endocrinology & Metabolism
Aaron M. Hosios, Meghan E. Wilkinson, Molly C. McNamara, Krystle C. Kalafut, Margaret E. Torrence, John M. Asara, Brendan D. Manning
Summary: Inhibition of mTORC1 leads to accumulation of intracellular triglycerides through lysosome-dependent hydrolysis of phospholipid fatty acids. The liberated fatty acids can be used for triglyceride synthesis or beta-oxidation.
Article
Multidisciplinary Sciences
Yui Kotani, Mami Sumiyoshi, Megumi Sasada, Toshio Watanabe, Satoshi Matsuda
Summary: This study reveals that Arf1 plays an important role in the activation of mTORC1 and cell proliferation in mast cells, but has little impact on degranulation and cytokine secretion. This finding suggests the potential of Arf1 as a therapeutic target for mast cell proliferative disorders.
SCIENTIFIC REPORTS
(2022)
Editorial Material
Urology & Nephrology
Editorial Eugene Shenderov, Emmanuel S. Antonarakis
Article
Oncology
Smruthy Sivakumar, Dexter X. Jin, Ruchita Rathod, Jeffrey Ross, Lewis C. Cantley, Maurizio Scaltriti, Jessica W. Chen, Katherine E. Hutchinson, Timothy R. Wilson, Ethan S. Sokol, Neil Vasan
Summary: The purpose of this study was to characterize the tissue-specific and molecular subclasses of multiple PIK3CA mutations and their impact on therapeutic outcomes. The results showed that multi-PIK3CA mutations accounted for 11% of all PIK3CA-mutant tumors and were enriched in breast and gynecologic cancers. These mutations frequently occurred in cis on the same allele and at characteristic positions across tumor types. Different classes of multi-PIK3CA mutant estrogen receptor-positive, HER2-negative breast cancers responded similarly to PI3K inhibition.
CLINICAL CANCER RESEARCH
(2023)
Article
Multidisciplinary Sciences
Miriam Saponaro, Sina Flottmann, Markus Eckstein, Oliver Hommerding, Niklas Kluemper, Dillon Corvino, Sana Hosni, Anja Schmidt, Nicolas Moenig, Doris Schmidt, Joerg Ellinger, Marieta Toma, Glen Kristiansen, Tobias Bald, Andrea Alimonti, Manuel Ritter, Michael Hoelzel, Abdullah Alajati
Summary: The poor prognosis of advanced urothelial carcinoma (UC) and the need for improved treatment have led researchers to investigate the role of CUB domain containing protein 1 (CDCP1) in UC. They found that CDCP1 is highly expressed in advanced UC and its overexpression is associated with shorter overall survival. Experiments with organoids and cell lines demonstrated that CDCP1 plays an oncogenic role by activating the MAPK/ERK pathway and promoting proliferation and migration. Targeting CDCP1 could be a rational therapeutic strategy for advanced UC.
SCIENTIFIC REPORTS
(2023)
Article
Oncology
Nicolo Bancaro, Bianca Cali, Martina Troiani, Angela Rita Elia, Rydell Alvarez Arzola, Giuseppe Attanasio, Ping Lai, Mateus Crespo, Bora Gurel, Rita Pereira, Christina Guo, Simone Mosole, Daniela Brina, Mariantonietta D'Ambrosio, Emiliano Pasquini, Clarissa Spataro, Elena Zagato, Andrea Rinaldi, Mattia Pedotti, Simona Di Lascio, Francesco Meani, Monica Montopoli, Matteo Ferrari, Andrea Gallina, Luca Varani, Ricardo Pereira Mestre, Marco Bolis, Silke Gillessen Sommer, Johann de Bono, Arianna Calcinotto, Andrea Alimonti
Summary: Tumor cells promote the recruitment of immunosuppressive neutrophils, a subset of myeloid cells driving immune suppression, tumor proliferation, and treatment resistance. We have identified a subset of neutrophils that have upregulated expression of cellular senescence markers and persist in the tumor microenvironment. These senescent-like neutrophils express TREM2 and are more immunosuppressive and tumor-promoting than canonical immunosuppressive neutrophils.
Article
Cell Biology
Rydell Alvarez-Arzola, Nicolo Bancaro, Ping Lai, Giuseppe Attanasio, Laura Pellegrini, Martina Troiani, Manuel Colucci, Simone Mosole, Emiliano Pasquini, Andrea Alimonti, Circe Mesa
Summary: Androgen deprivation therapy (ADT) is a standard treatment for prostate cancer, but some patients develop castration-resistant prostate cancer (CRPC). Activating ex vivo-activated macrophages as immunotherapy shows potential for treating CRPC by inhibiting tumor growth and reducing angiogenesis and proliferation.
CELL COMMUNICATION AND SIGNALING
(2023)
Review
Clinical Neurology
Maurizio Fava, Stephen M. M. Stahl, Sara De Martin, Andrea Mattarei, Ezio Bettini, Stefano Comai, Andrea Alimonti, Francesco Bifari, Luca Pani, Franco Folli, Clotilde Guidetti, Alberto Furlan, Jacopo Sgrignani, Patrizia Locatelli, Andrea Cavalli, Cedric O'Gorman, Sergio Traversa, Charles E. E. Inturrisi, Marco Pappagallo, Paolo L. L. Manfredi
Summary: This review article discusses recent studies on the development of esmethadone as a potential new drug. Esmethadone is a member of the pharmacological class of uncompetitive NMDAR antagonists and has shown efficacy for MDD and other diseases. The article also compares esmethadone with other NMDAR antagonists. It presents data from in silico, in vitro, in vivo, and clinical studies that contribute to our understanding of the role of these receptors in neural plasticity in health and disease. The efficacy of NMDAR antagonists as rapid antidepressants has implications for the neurobiology of MDD and other neuropsychiatric disorders.
EUROPEAN ARCHIVES OF PSYCHIATRY AND CLINICAL NEUROSCIENCE
(2023)
Article
Oncology
Arkaitz Carracedo
Summary: The process of cellular transformation involves the acquisition of key features known as hallmarks of cancer, which are supported by molecular alterations and changes in the microenvironment. Cellular metabolism is a crucial link between a cell and its environment, and metabolic adaptation is an increasingly important research field in cancer biology.
MOLECULAR ONCOLOGY
(2023)
Editorial Material
Oncology
Luis A. Diaz, Lewis C. Cantley
Correction
Multidisciplinary Sciences
Miriam Saponaro, Sina Flottmann, Markus Eckstein, Oliver Hommerding, Niklas Kluemper, Dillon Corvino, Sana Hosni, Anja Schmidt, Nicolas Moenig, Doris Schmidt, Joerg Ellinger, Marieta Toma, Glen Kristiansen, Tobias Bald, Andrea Alimonti, Manuel Ritter, Michael Hoelzel, Abdullah Alajati
SCIENTIFIC REPORTS
(2023)
Article
Biochemistry & Molecular Biology
Jan Pencik, Cecile Philippe, Michaela Schlederer, Emine Atas, Matteo Pecoraro, Sandra Grund-Groeschke, Wen (Jess) Li, Amanda Tracz, Isabel Heidegger, Sabine Lagger, Karolina Trachtova, Monika Oberhuber, Ellen Heitzer, Osman Aksoy, Heidi A. Neubauer, Bettina Wingelhofer, Anna Orlova, Nadine Witzeneder, Thomas Dillinger, Elisa Redl, Georg Greiner, David D'Andrea, Johnny R. Ostman, Simone Tangermann, Ivana Hermanova, Georg Schaefer, Felix Sternberg, Elena E. Pohl, Christina Sternberg, Adam Varady, Jaqueline Horvath, Dagmar Stoiber, Tim I. Malcolm, Suzanne D. Turner, Eileen E. Parkes, Brigitte Hantusch, Gerda Egger, Stefan Rose-John, Valeria Poli, Suneil Jain, Chris W. D. Armstrong, Gregor Hoermann, Vincent Goffin, Fritz Aberger, Richard Moriggl, Arkaitz Carracedo, Cathal McKinney, Richard D. Kennedy, Helmut Klocker, Michael R. Speicher, Dean G. Tang, Ali A. Moazzami, David M. Heery, Marcus Hacker, Lukas Kenner
Summary: PTEN and STAT3 are frequently co-deleted genes in metastatic prostate cancer (mPCa). STAT3 controls mPCa through the LKB1/pAMPK/mTORC1/CREB signaling pathway, and metformin can inhibit mPCa growth.
Article
Urology & Nephrology
Nicolo Pernigoni, Christina Guo, Lewis Gallagher, Wei Yuan, Manuel Colucci, Martina Troiani, Lei Liu, Luisa Maraccani, Ilaria Guccini, Denis Migliorini, Johann de Bono, Andrea Alimonti
Summary: The microbiota, a complex and dynamic population of microorganisms in the human body, has been found to play a role in the development and progression of prostate cancer. Specific microbial species in the urine and gut have been associated with an increased risk of prostate cancer, but the causal mechanisms are still not well understood. Mechanistic evidence suggests that bacterial generation of genotoxins and production of androgenic steroids by the gut microbiota may contribute to prostate carcinogenesis and therapeutic resistance. These findings open up potential avenues for the diagnosis and treatment of prostate cancer by profiling and modulating the host microbiota.
NATURE REVIEWS UROLOGY
(2023)
Article
Multidisciplinary Sciences
Ilaria Guccini, Guanghui Tang, Trang Thuy To, Laura Di Rito, Solange Le Blanc, Oliver Strobel, Mariantonietta D'Ambrosio, Emiliano Pasquini, Marco Bolis, Pamuditha Silva, Hasan Ali Kabakci, Svenja Godbersen, Andrea Alimonti, Gerald Schwank, Markus Stoffel
Summary: The rate-limiting enzyme of fructose metabolism, KHK, is found to be a driver of pancreatic cancer (PDAC) development. Fructose triggers the activation of KHK and induces the expression of fructolytic genes in PDAC. Genetic inactivation of KhkC enhances the survival of KPC-driven PDAC and reduces the viability and growth of KPC cells, likely through impairing KRAS-MAPK pathway and mTORC signaling. These findings suggest that inhibiting KHK could be a promising therapeutic strategy for pancreatic cancer.
Editorial Material
Biochemistry & Molecular Biology
Ying Mei, Qinglei Hang, Hongqi Teng, Fan Yao, Mei-Ku ang Chen, Mien-Chie Hung, Yutong Sun, Li Ma
Article
Oncology
Daniela Brina, Adele Ponzoni, Martina Troiani, Bianca Cali, Emiliano Pasquini, Giuseppe Attanasio, Simone Mosole, Michela Mirenda, Mariantonietta D'Ambrosio, Manuel Colucci, Ilaria Guccini, Ajinkya Revandkar, Abdullah Alajati, Toma Tebaldi, Deborah Donzel, Fabio Lauria, Nahjme Parhizgari, Aurora Valdata, Martino Maddalena, Arianna Calcinotto, Marco Bolis, Andrea Rinaldi, Simon Barry, Jan Hendrik Rueschoff, Marianna Sabbadin, Semini Sumanasuriya, Mateus Crespo, Adam Sharp, Wei Yuan, Mathew Grinu, Alexandra Boyle, Cynthia Miller, Lloyd Trotman, Nicolas Delaleu, Matteo Fassan, Holger Moch, Gabriella Viero, Johann de Bono, Andrea Alimonti
Summary: In prostate cancer, the secretome is rewired at the translational level to recruit MDSCs, with Hgf, Spp1, and Bgn identified as key regulators. By inhibiting the MNK/eIF4E and AKT pathways, this study provides a therapeutic strategy that combines translation inhibition with immunotherapy to restore immune surveillance in prostate cancer.
Review
Oncology
Yang Zhao, Marisela Sheldon, Yutong Sun, Li Ma
Summary: The Hippo pathway plays a crucial role in regulating cell growth, tumor spread, and resistance to cancer treatments. Dysregulation of this pathway can contribute to tumor growth, metastasis, and therapy resistance. This review focuses on the involvement of the Hippo pathway in cancer, discussing the role of YAP/TAZ-TEAD-mediated gene regulation, mechanisms contributing to metastasis and therapy resistance, and advances in therapeutic strategies targeting this pathway. It also addresses ongoing controversies and provides perspectives on specific debated topics in this field.