Article
Cell Biology
Catherine Vander Linden, Cyril Corbet, Estelle Bastien, Ruben Martherus, Celine Guilbaud, Laurenne Petit, Loris Wauthier, Axelle Loriot, Charles De Smet, Olivier Feron
Summary: Metabolic plasticity in cancer cells presents challenges in using metabolism-targeting agents, but drug-induced metabolic rewiring can uncover vulnerabilities that may be exploited for treatment efficacy.
Article
Biochemistry & Molecular Biology
Juan B. Orsi, Lara S. Araujo, Pedro P. M. Scariot, Emanuel E. C. Polisel, Luisa O. Cardoso, Claudio A. Gobatto, Fulvia B. Manchado-Gobatto
Summary: Although the critical velocity (CV) protocol has been used to determine aerobic capacity in rodents, there is a lack of studies comparing CV with maximal lactate steady state intensity (iMLSS) in mice. This study aimed to compare and correlate CV with iMLSS in running mice and evaluate their physiological responses and muscle MCT1 and MCT4. The results showed that CV was significantly correlated with iMLSS. The content of MCT1 and MCT4 in the muscles did not play a decisive role in determining the time to exhaustion at CV intensity.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2023)
Article
Pharmacology & Pharmacy
Yuto Mukai, Atsushi Yamaguchi, Tomoya Sakuma, Takanobu Nadai, Ayako Furugen, Katsuya Narumi, Masaki Kobayashi
Summary: This study evaluated the expression and role of MCT1, MCT2, and MCT4 in l-lactate uptake in hepatocellular carcinoma cells. Results showed that both MCT1 and MCT4 were involved in l-lactate transport in HepG2 and Huh-7 cells at pH 6.0, while MCT2 had no effect.
BIOPHARMACEUTICS & DRUG DISPOSITION
(2022)
Article
Biochemistry & Molecular Biology
Aarti Kawatkar, Roger A. Clark, Lorna Hopcroft, Debora Ann Roaquin, Ronald Tomlinson, Andrea M. Zuhl, Gillian M. Lamont, Jason G. Kettle, Susan E. Critchlow, M. Paola Castaldi, Frederick W. Goldberg, Andrew X. Zhang
Summary: Lactic acid transport inhibition is pursued as a therapeutic approach for cancers. We identified and optimized compounds that inhibit intracellular lactic acid efflux and developed three assays to measure cellular target engagement. These data demonstrate the power of orthogonal chemical biology methods to determine cellular target engagement, particularly for proteins not readily amenable to traditional biophysical methods.
ACS CHEMICAL BIOLOGY
(2023)
Article
Medicine, Research & Experimental
Hu Zhao, Yuan Chen, You-Ping Liao, Hai-Mei Chen, Qiu-Hong Yang, Yin Xiao, Jing Luo, Zhen-Zhen Chen, Lai Yi, Guo-Yu Hu
Summary: This study found that the expression of MCT1 and MCT4 is increased in patients with T-cell lymphoma (TCL) and may predict poor prognosis. Inhibiting MCT1 could be a novel treatment strategy for TCL.
CLINICAL AND EXPERIMENTAL MEDICINE
(2023)
Article
Oncology
Tatsuo Okui, Masahiro Hiasa, Kazuaki Hasegawa, Tomoya Nakamura, Kisho Ono, Soichiro Ibaragi, Takahiro Kanno, Akira Sasaki, Toshiyuki Yoneda
Summary: Breast cancer bone metastasis causes bone pain and the mechanism behind it is poorly understood. This study used a mouse model and found that lactate released from breast cancer cells through MCT4 activates GPR81 in sensory neurons, contributing to the induction of breast cancer bone pain. Silencing MCT4 and GPR81 reduced bone pain and the expression of molecular indicators of neuron excitation in sensory neurons.
INTERNATIONAL JOURNAL OF ONCOLOGY
(2023)
Article
Ophthalmology
Celia M. Bisbach, Daniel T. Hass, Eric D. Thomas, Timothy J. Cherry, James B. Hurley
Summary: In this study, the role of MCT1 in succinate export from the retina and succinate import into the RPE was investigated. The results showed that MCT1 facilitates succinate export from the retina, while an unidentified non-MCT transporter mediates succinate import into the RPE.
INVESTIGATIVE OPHTHALMOLOGY & VISUAL SCIENCE
(2022)
Article
Multidisciplinary Sciences
Katia Monsorno, Kyllian Ginggen, Andranik Ivanov, An Buckinx, Arnaud L. Lalive, Anna Tchenio, Sam Benson, Marc Vendrell, Angelo D'Alessandro, Dieter Beule, Luc Pellerin, Manuel Mameli, Rosa Chiara Paolicelli
Summary: Microglia can import lactate as a metabolic fuel and lactate promotes lysosomal acidification in these cells. Loss of MCT4 in microglia leads to impaired synapse pruning and behavioral defects.
NATURE COMMUNICATIONS
(2023)
Article
Chemistry, Medicinal
Yang Wang, Liuxin Qin, Weiwei Chen, Qing Chen, Jin Sun, Gang Wang
Summary: This article summarizes the recent progress in therapeutic strategies targeting MCT1, MCT4, and LAT1 in tumors, including protein structures, relationships with cancer, drug targeting, and delivery strategies. The dual targeted strategy is proposed to enhance the effect on tumor proliferation.
EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
(2021)
Article
Multidisciplinary Sciences
Keizo Takenaga, Nobuko Koshikawa, Miho Akimoto, Yasutoshi Tatsumi, Jason Lin, Makiko Itami, Hiroki Nagase
Summary: Pathogenic mitochondrial NADH dehydrogenase gene mutations enhance the invasion and metastasis of cancer cells, while overexpression of monocarboxylate transporter 4 is involved in cancer cell proliferation and survival. The expression of MCT4 is regulated by pathogenic ND mutations and has potential as a biomarker and therapeutic target in metastatic tumors with these mutations.
SCIENTIFIC REPORTS
(2021)
Article
Cell Biology
Meng Zhao, Chen Huang, Lexin Yang, Boyu Pan, Shuting Yang, Jiao Chang, Yu Jin, Gang Zhao, Dongsheng Yue, Shuo Qie, Li Ren
Summary: SYVN1 E3 ubiquitin ligase post-translationally regulates the localization and function of MCT4, affecting metabolic reprogramming in tumor cells and predicting poor prognosis in patients with LUAD.
CELL DEATH & DISEASE
(2023)
Article
Oncology
Vera Miranda-Goncalves, Celine S. Goncalves, Sara Granja, Joana Vieira de Castro, Rui M. Reis, Bruno M. Costa, Fatima Baltazar
Summary: The overexpression of MCT1 is associated with poor prognosis in GBM patients. Inhibiting MCT1 can slow down tumor growth and enhance response to temozolomide treatment in GBM.
Article
Pathology
Jung-Woo Choi, Youngseok Lee, Hyunchul Kim, Hyun Yee Cho, Soo Kee Min, Young-Sik Kim
Summary: In solid tumors and malignant lymphomas, lactate transport is regulated by different monocarboxylate transporters. Malignant lymphomas with ALK(+) ALCL show a unique metabolic phenotype characterized by high coexpression of MCT1 and MCT4 in tumor cells. Immunostaining for MCT4, together with ALK, can be useful for the differential diagnosis of ALK(-) ALCL and peripheral T-cell lymphoma. Dual targeting of MCT1 and MCT4 may be an appropriate therapeutic approach for ALK(+) ALCL.
AMERICAN JOURNAL OF SURGICAL PATHOLOGY
(2022)
Article
Oncology
Atsushi Yamaguchi, Yuto Mukai, Tomoya Sakuma, Ayako Furugen, Katsuya Narumi, Masaki Kobayashi
Summary: This study found that statins can inhibit the transport activities of hMCT1, hMCT2, and hMCT4, with atorvastatin showing potent isoform-selective inhibition of hMCT2. Docking simulation revealed that atorvastatin could interact with a specific site, potentially leading to the discovery of more potent hMCT2-selective inhibitors. These findings are important for understanding the inhibitory mechanism of statins against hMCT1, hMCT2, and hMCT4, and may contribute to the development of novel anticancer agents.
ANTICANCER RESEARCH
(2023)
Article
Biochemistry & Molecular Biology
Xiucheng Liu, Hao Qin, Li Zhang, Caili Jia, Zhixiang Chao, Xichun Qin, Hao Zhang, Chang Chen
Summary: The effects of 60% oxygen exposure on the pH of lung cancer cells were evaluated in this study. The results showed that hyperoxia exposure reduced intracellular pH, leading to a decrease in the proliferation, invasion, and epithelial-to-mesenchymal transition of lung cancer cells. MCT1 was found to mediate intracellular lactate accumulation and acidification of the cells under hyperoxic conditions.
Article
Chemistry, Multidisciplinary
Deborah K. Shoemark, Charlotte K. Colenso, Christine Toelzer, Kapil Gupta, Richard B. Sessions, Andrew D. Davidson, Imre Berger, Christiane Schaffitzel, James Spencer, Adrian J. Mulholland
Summary: The study found that linoleate and dexamethasone can stabilize the conformation of the SARS-CoV-2 spike protein, reducing its interaction with ACE2, while cholesterol may expose the receptor-binding domain. Furthermore, steroids, retinoids, and vitamins were identified as potential ligands that may stabilize the closed conformation.
ANGEWANDTE CHEMIE-INTERNATIONAL EDITION
(2021)
Article
Biochemistry & Molecular Biology
Chloe A. N. Gerak, Sophia Y. Cho, Maxim Kolesnikov, Mark Okon, Michael E. P. Murphy, Richard B. Sessions, Michel Roberge, Lawrence P. McIntosh
Summary: ETV6 is a transcriptional repressor that self-associates through its PNT domain to aid DNA binding, often involved in chromosomal translocations generating active oncogenic proteins. Studies demonstrate that targeting the hydrophobic or charged regions with small molecules could potentially inhibit ETV6 PNT domain polymerization.
JOURNAL OF BIOLOGICAL CHEMISTRY
(2021)
Article
Biochemical Research Methods
Chloe A. N. Gerak, Si Miao Zhang, Aruna D. Balgi, Ivan J. Sadowski, Richard B. Sessions, Lawrence P. McIntosh, Michel Roberge
Summary: ETV6, an ETS family transcriptional repressor, can lead to various cancers when its PNT domain is fused to multiple protein tyrosine kinases. Currently, there are no known small-molecule inhibitors targeting ETV6 PNT domain polymerization, but experimental and computational approaches have been developed to identify such compounds.
Article
Biochemistry & Molecular Biology
Sarah M. Smith, Gabrielle Larocque, Katherine M. Wood, Kyle L. Morris, Alan M. Roseman, Richard B. Sessions, Stephen J. Royle, Corinne J. Smith
Summary: The interaction between Clathrin and the AP2 complex plays a crucial role in coated-pit assembly, with a beta 2 appendage able to bind in at least two positions in the clathrin cage. This multi-modal binding is shown to be a fundamental property of clathrin-AP2 interactions.
Article
Biochemistry & Molecular Biology
Aysha B. Mezoughi, Chiara M. Costanzo, Gregor M. Parker, Enas M. Behiry, Alan Scott, Andrew C. Wood, Sarah E. Adams, Richard B. Sessions, E. Joel Loveridge
Summary: Lytic transglycosylases like Slt35 are potential targets for novel antibacterial agents. Thionine acetate was found to be a weak inhibitor of both Slt35 and lysozyme, and also enhanced the efficacy of ampicillin against E. coli.
Article
Chemistry, Multidisciplinary
Shisanupong Anukanon, Pornkanok Pongpamorn, Wareepat Tiyabhorn, Jaruwan Chatwichien, Worawat Niwetmarin, Richard B. Sessions, Somsak Ruchirawat, Nopporn Thasana
Summary: The study investigated the structure-activity relationship of C(2)-functionalized and O- or N-methyl-substituted huperzine A derivatives and performed in vitro activity evaluation.
Article
Biochemistry & Molecular Biology
Erik J. B. Landin, Christopher Williams, Sara A. Ryan, Alice Bochel, Nahida Akter, Christina Redfield, Richard B. Sessions, Neesha Dedi, Richard J. Taylor, Matthew P. Crump
Summary: AGP is an abundant blood plasma protein with immunomodulatory functions that can affect the pharmacokinetics of small molecule drugs. Some kinase inhibitors like UCN-01 have poor pharmacokinetics due to binding to AGP variants AGP1 and AGP2. Solving the structure of the AGP2-UCN-01 complex revealed the precise binding mode and potential for rational redesign of small molecules to improve tissue distribution.
JOURNAL OF BIOLOGICAL CHEMISTRY
(2021)
Article
Pharmacology & Pharmacy
Nokomis Ramos-Gonzalez, Sam Groom, Katy J. Sutcliffe, Sukhvinder Bancroft, Chris P. Bailey, Richard B. Sessions, Graeme Henderson, Eamonn Kelly
Summary: The illicit use of fentanyl-like drugs and the resulting overdose deaths is a major problem. This study compared the efficacy and signaling bias of different fentanyls, and found that carfentanil is biased towards beta-arrestin.
BRITISH JOURNAL OF PHARMACOLOGY
(2023)
Article
Cell Biology
Natalia Jimenez-Moreno, Madhu Kollareddy, Petros Stathakos, Joanna J. Moss, Zurine Anton, Deborah K. Shoemark, Richard B. Sessions, Ralph Witzgall, Maeve Caldwell, Jon D. Lane
Summary: LMX1A and LMX1B are essential for dopaminergic neuronal differentiation and survival, and they also act as transcription factors for cellular stress protection through autophagy. Their suppression impairs autophagy response and mitochondrial function, while their inducible overexpression protects against rotenone toxicity in vitro.
JOURNAL OF CELL BIOLOGY
(2023)
Article
Biochemistry & Molecular Biology
Samia A. Elseginy, A. Sofia F. Oliveira, Deborah K. Shoemark, Richard B. Sessions
Summary: This research identified a novel compound that inhibits microtubule protein and shows potential anticancer activity. It suppresses cancer cell proliferation, induces cell cycle arrest and apoptosis, and has low toxicity. The compound blocks tubulin polymerization and activates caspase 9, leading to apoptosis.
RSC MEDICINAL CHEMISTRY
(2022)
Article
Biochemistry & Molecular Biology
Fruzsina Hobor, Zsofia Hegedus, Amaurys Avila Ibarra, Vencel L. Petrovicz, Gail J. Bartlett, Richard B. Sessions, Andrew J. Wilson, Thomas A. Edwards
Summary: The hypoxic response is crucial for cell function and vital in the growth and survival of solid tumors. HIF-1 regulates this response by activating over 100 genes responsible for adapting to hypoxia, making it a potential target for anticancer drug discovery. This study investigates the sequence determinants of the binding between HIF-1 alpha and p300, as well as negative regulators of HIF-1 alpha such as CITED2. The findings suggest that the HIF-1 alpha sequence is highly tolerant to sequence variation, and the binding interaction is controlled by backbone interactions and ligand folding.
RSC CHEMICAL BIOLOGY
(2022)
Article
Chemistry, Multidisciplinary
H. T. Henry Chan, Marc A. Moesser, Rebecca K. Walters, Tika R. Malla, Rebecca M. Twidale, Tobias John, Helen M. Deeks, Tristan Johnston-Wood, Victor Mikhailov, Richard B. Sessions, William Dawson, Eidarus Salah, Petra Lukacik, Claire Strain-Damerell, C. David Owen, Takahito Nakajima, Katarzyna Swiderek, Alessio Lodola, Vicent Moliner, David R. Glowacki, James Spencer, Martin A. Walsh, Christopher J. Schofield, Luigi Genovese, Deborah K. Shoemark, Adrian J. Mulholland, Fernanda Duarte, Garrett M. Morris
Summary: Through various biophysical and crystallographic data analysis, researchers investigated the molecular features underlying the binding of SARS-CoV-2's main protease to its natural cleavage sites, highlighting the importance of interactions between substrates and enzymes. They designed peptides with improved affinity to competitively inhibit M-pro, providing new insights and opportunities for the development of M-pro inhibitors as anti-COVID-19 drugs.
Article
Biochemistry & Molecular Biology
Kristina Hetherington, Som Dutt, Amaurys A. Ibarra, Emma E. Cawood, Fruzsina Hobor, Derek N. Woolfson, Thomas A. Edwards, Adam Nelson, Richard B. Sessions, Andrew J. Wilson
Summary: The study introduces a computationally validated workflow for modifying the sequence of peptide inhibitors of protein-protein interactions.
RSC CHEMICAL BIOLOGY
(2021)
Article
Chemistry, Multidisciplinary
Sergio Celis, Fruzsina Hobor, Thomas James, Gail J. Bartlett, Amaurys A. Ibarra, Deborah K. Shoemark, Zsofia Hegedus, Kristina Hetherington, Derek N. Woolfson, Richard B. Sessions, Thomas A. Edwards, David M. Andrews, Adam Nelson, Andrew J. Wilson
Summary: The study presents a general approach to discover orthosteric PPI inhibitors that mimic specific secondary protein structures, validated through experimental examples. Low μM activity selective PPI inhibitors were discovered for two unrelated PPIs, with defined structure-activity relationships established through hit expansion. The approach is believed to have the potential to enable the discovery of inhibitors for a wide range of unrelated secondary structure-mediated PPIs.
Article
Chemistry, Multidisciplinary
Zsofia Hegedus, Fruzsina Hobor, Deborah K. Shoemark, Sergio Celis, Lu-Yun Lian, Chi H. Trinh, Richard B. Sessions, Thomas A. Edwards, Andrew J. Wilson
Summary: This study describes an alternative approach using dynamic ligation screening to identify small-molecule replacements for beta-strand mediated protein-protein interactions. The findings demonstrate the effectiveness of this method in identifying and validating peptide hybrids with selective inhibitory effects.