Immunometabolic actions of trabectedin and lurbinectedin on human macrophages: relevance for their anti-tumor activity
Por:
Povo-Retana A, Fariñas M, Landauro-Vera R, Mojena M, Alvarez-Lucena C, Fernández-Moreno MA, Castrillo A, de la Rosa Medina JV, Sánchez-García S, Foguet C, Mas F, Marín-del Barrio S, Cascante M and Boscá L
Publicada:
22 ago 2023
Ahead of Print:
22 ago 2023
Resumen:
In recent years, the central role of cell bioenergetics in regulating immune cell function and fate has been recognized, giving rise to the interest in immunometabolism, an area of research focused on the interaction between metabolic regulation and immune function. Thus, early metabolic changes associated with the polarization of macrophages into pro-inflammatory or pro-resolving cells under different stimuli have been characterized. Tumor-associated macrophages are among the most abundant cells in the tumor microenvironment; however, it exists an unmet need to study the effect of chemotherapeutics on macrophage immunometabolism. Here, we use a systems biology approach that integrates transcriptomics and metabolomics to unveil the immunometabolic effects of trabectedin (TRB) and lurbinectedin (LUR), two DNA-binding agents with proven antitumor activity. Our results show that TRB and LUR activate human macrophages toward a pro-inflammatory phenotype by inducing a specific metabolic rewiring program that includes ROS production, changes in the mitochondrial inner membrane potential, increased pentose phosphate pathway, lactate release, tricarboxylic acids (TCA) cycle, serine and methylglyoxal pathways in human macrophages. Glutamine, aspartate, histidine, and proline intracellular levels are also decreased, whereas oxygen consumption is reduced. The observed immunometabolic changes explain additional antitumor activities of these compounds and open new avenues to design therapeutic interventions that specifically target the immunometabolic landscape in the treatment of cancer.
Filiaciones:
Povo-Retana A:
Instituto de Investigaciones Biomédicas Alberto Sols, CSIC-UAM, Madrid, Spain
Fariñas M:
Department of Biochemistry and Molecular Biomedicine-Institute of Biomedicine (IBUB), Faculty of Biology, Universitat de Barcelona, Barcelona, Spain
Landauro-Vera R:
Instituto de Investigaciones Biomédicas Alberto Sols, CSIC-UAM, Madrid, Spain
Mojena M:
Instituto de Investigaciones Biomédicas Alberto Sols, CSIC-UAM, Madrid, Spain
Alvarez-Lucena C:
Instituto de Investigaciones Biomédicas Alberto Sols, CSIC-UAM, Madrid, Spain
Fernández-Moreno MA:
Instituto de Investigaciones Biomédicas Alberto Sols, CSIC-UAM, Madrid, Spain
Departamento de Bioquímica, Facultad de Medicina, Universidad Autónoma de Madrid, Madrid, Spain
Castrillo A:
Instituto de Investigaciones Biomédicas Alberto Sols, CSIC-UAM, Madrid, Spain
Unidad de Biomedicina (Unidad Asociada al CSIC) de la Universidad de Las Palmas de Gran Canaria, Las Palmas, Spain
de la Rosa Medina JV:
Unidad de Biomedicina (Unidad Asociada al CSIC) de la Universidad de Las Palmas de Gran Canaria, Las Palmas, Spain
Unidad Instituto Universitario de Investigaciones Biomédicas y Sanitarias (IUIBS) de la Universidad de Las Palmas de Gran Canaria, Las Palmas, Spain
Sánchez-García S:
Instituto de Investigaciones Biomédicas Alberto Sols, CSIC-UAM, Madrid, Spain
Foguet C:
British Heart Foundation Cardiovascular Epidemiology Unit, Department of Public Health and Primary Care, University of Cambridge, Cambridge, United Kingdom
Mas F:
Department of Material Science and Physical Chemistry & Research Institute of Theoretical and Computational Chemistry (IQTCUB), University of Barcelona, Barcelona, Spain
Marín-del Barrio S:
Department of Biochemistry and Molecular Biomedicine-Institute of Biomedicine (IBUB), Faculty of Biology, Universitat de Barcelona, Barcelona, Spain
CIBER of Hepatic and Digestive Diseases (CIBEREHD), Institute of Health Carlos III (ISCIII), Madrid, Spain
Cascante M:
Department of Biochemistry and Molecular Biomedicine-Institute of Biomedicine (IBUB), Faculty of Biology, Universitat de Barcelona, Barcelona, Spain
CIBER of Hepatic and Digestive Diseases (CIBEREHD), Institute of Health Carlos III (ISCIII), Madrid, Spain
Boscá L:
Instituto de Investigaciones Biomédicas Alberto Sols, CSIC-UAM, Madrid, Spain
Unidad de Biomedicina (Unidad Asociada al CSIC) de la Universidad de Las Palmas de Gran Canaria, Las Palmas, Spain
Centro de Investigación Biomédica en Red de Enfermedades Cardiovasculares (CIBERCV), Av. Monforte de Lemos, Madrid, Spain
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