One of the major hallmarks of cancer cells is a deficient ability to undergo cell death, particularly apoptosis. A deficient apoptosis response in cancer cells increases their malignancy, favoring accumulation of mutations and rendering tumor cells resistant to therapy. This implies that a therapeutic potential for cancer treatment may lie in potentiating apoptosis. Thus, apoptosis-targeted therapy can be a new and effective way to kill tumor cells. In this regard, we have found that death receptors as well as downstream signaling molecules are recruited into lipid raft membrane domains upon addition of some anticancer drugs, thus acting as the linchpin from which a potent apoptotic response is launched, and linking lipid rafts and cancer chemotherapy. Co-clustering of death receptors and membrane rafts regulates apoptosis and constitutes a novel anticancer target. In addition, lipid rafts act as scaffolds for additional proteins involved in dictating cell fate, leading to apoptosis or survival. Translocation of Fas/CD95 death receptor into membrane rafts can be rendered independently of Fas/CD95 ligand, thus opening new prospects for pharmacological intervention. Furthermore, additional subcellular structures, particularly mitochondria and endoplasmic reticulum, play a major role in regulating cell death, and thereby can also be targets in cancer therapy. The antitumor compounds collectively known as alkylphospholipid analogs (APLs) are the first lipid raft-targeted drugs that promote apoptosis in a number of cancer cells both in vitro and in vivo. The antitumor ether lipid edelfosine, considered as the prototypic APL molecule, induces apoptosis through a raft-mediated process in several hematological cancers as well as through an endoplasmic reticulum stress response in solid tumor cells. Both signaling routes involve mitochondria as a critical organelle in the cell death outcome. In addition, we are interested in understanding the role of inflammation in cancer, and how arginase, highly abundant in neutrophils, affects cancer development.
|Faustino Mollinedo Garcia|
|Consuelo Gajate Fraile|
|Alejandro Martin Roncero|
|Ramón Romero Varo|
Gajate, C., Mollinedo, F. . Lipid raft-mediated Fas/CD95 apoptotic signaling in leukemic cells and normal leukocytes and therapeutic implications. Journal of Leukocyte Biology. 98:739-759.
Cuesta-Marbán, Á., Botet, J., Czyz, O., Cacharro, L.M., Gajate, C., Hornillos, V., Delgado, J., Zhang, H., Amat-Guerri, F., Acuña, A.U., McMaster, C.R., Revuelta, J.L., Zaremberg, V., Mollinedo, F. . Drug uptake, lipid rafts, and vesicle trafficking modulate resistance to an anticancer lysophosphatidylcholine analogue in yeast. Journal of Biological Chemistry. 288:8405-8418.
Varela-M, R.E., Villa-Pulgarin, J.A., Yepes, E., Müller, I., Modolell, M., Muñoz, D.L., Robledo, S.M., Muskus, C.E., López-Abán, J., Muro, A., Vélez, I.D., Mollinedo, F. . In vitro and in vivo efficacy of ether lipid edelfosine against Leishmania spp. and SbV-resistant parasites. PLoS Neglected Tropical Diseases. 6:-.
Gajate, C., Matos-Da-Silva, M., Dakir, E.L.-H., Fonteriz, R.I., Alvarez, J., Mollinedo, F. . Antitumor alkyl-lysophospholipid analog edelfosine induces apoptosis in pancreatic cancer by targeting endoplasmic reticulum. Oncogene. 31:2627-2639.
García-Navas, R., Munder, M., Mollinedo, F. . Depletion of L-arginine induces autophagy as a cytoprotective response to endoplasmic reticulum stress in human T lymphocytes. Autophagy. 8:1557-1576.
Mollinedo, F., De La Iglesia-Vicente, J., Gajate, C., Estella-Hermoso De Mendoza, A., Villa-Pulgarin, J.A., Campanero, M.A., Blanco-Prieto, M.J. . Lipid raft-targeted therapy in multiple myeloma. Oncogene. 29:3748-3757.
Gajate, C., Mollinedo, F. . Edelfosine and perifosine induce selective apoptosis in multiple myeloma by recruitment of death receptors and downstream signaling molecules into lipid rafts. Blood. 109:711-719.
Mollinedo, F., Calafat, J., Janssen, H., Martín-Martín, B., Canchado, J., Nabokina, S.M., Gajate, C. . Combinatorial SNARE complexes modulate the secretion of cytoplasmic granules in human neutrophils. Journal of Immunology. 177:2831-2841.
Gajate, C., Del Canto-Jañez, E., Acuña, A.U., Amat-Guerri, F., Geijo, E., Santos-Beneit, A.M., Veldman, R.J., Mollinedo, F. . Intracellular triggering of Fas aggregation and recruitment of apoptotic molecules into Fas-enriched rafts in selective tumor cell apoptosis. Journal of Experimental Medicine. 200:353-365.
RESEARCH GRANTS IN PROGRESS
2011-2016. “Integrating chemical approaches to treat pancreatic cancer: making new leads for a cure” (HEALTH-F2-2011-256986, PANACREAS). (Coordinator: Georg Feldmann ; Workpackage PI: Faustino Mollinedo) European Union.
2013-2016. Red Temática en Investigación Cooperativa en Cáncer (RD12/0036/0065). (PI: Faustino Mollinedo). Instituto de Salud Carlos III.
2015-2017. “Lipid rafts, cancer stem cells y microentorno tumoral inflamatorio en la terapia del cáncer: analogos alquilfosfolipidos como agentes líder en terapias dirigidas a lipid rafts” (SAF2014-59716-R). (PI: Faustino Mollinedo). Ministerio de Economia y Competitividad.
We first reported the recruitment of Fas/CD95 receptor in lipid rafts as a new way to regulate apoptosis in cancer cells, thus identifying lipid rafts as a novel therapeutic target. This finding opened a new therapeutic approach in cancer treatment, and we are devoted to uncover the role of lipid rafts in regulating cell death and survival. We have coined the term CASMER, as an acronym for “cluster of apoptotic signaling molecule-enriched rafts”, to refer to the recruitment of death receptors together with downstream apoptotic signaling molecules in aggregated rafts, thus leading to a raft-based supramolecular entity playing a major role in apoptosis regulation. We are mainly involved in the study of the mechanism of action of APLs as anticancer drugs against both hematological and solid tumors, especially the ether phospholipid edelfosine, which is considered as the first lipid raft-targeted drug. Furthermore, major interests in our lab also include the search for new drugs and therapeutic targets in pancreatic cancer, as well as the elucidation of the role of cancer stem cells in pancreatic cancer, and other additional gastrointestinal cancers, as a major target in cancer therapy. In addition, we are studying neutrophil development to understand how a proapoptotic phenotype is generated. We are also analyzing new pro-cell death routes in additional biological systems, including yeast and C. elegans, which in turn are being used as model organisms to uncover the mechanism of action of APLs. Overall, our major focus is the identification of novel targets, and the design of new therapeutic agents and approaches, to eventually induce the onset of cell death in tumor cells as an apoptosis- or cell death-targeted therapy in cancer. Particular emphasis is placed on the role of subcellular structures, including lipid raft membrane domains, endoplasmic reticulum and mitochondria, as major targets for cancer therapy and in the mechanism of action of APLs. In addition, we are analyzing how APLs can promote distinct types of cell death in different cancer cells, and trying to understand the triggers and signaling cross-talk controlling cell death commitment. As a result of the ability of edelfosine to promote cell death in different biological systems, we are also studying the underlying mechanisms involved in the antiparasitic action of this ether lipid.
– Characterization and role of membrane rafts in apoptosis induction and cancer chemotherapy.
– Functional relationship between membrane rafts and subcellular structures affecting cell fate.
– Lipid metabolism in cancer cell development and therapy.
– Search for novel anticancer drugs targeting cell death in tumor cells.
– Mechanism of action of antitumor ether lipids (also known as alkylphospholipid analogs, APLs) as pro-cell death agents against cancer cells. Identification of distinct types of cell death induced by APLs.
- Analysis of cell death in cancer stem cells and cancer stem cell targeting in cancer therapy.
– Role and mechanisms of action of antitumor APLs as drugs for additional biomedical applications (inflammatory diseases, leishmaniasis, additional parasitic diseases).
– Inflammation and cancer relationship.
– Role of neutrophils and arginase in cancer.
– Neutrophils as a model system for the search of new therapeutic targets in cancer.
– Targeting of cancer stem cells.
– Use of additional biological systems (yeast, Caenorhabditis elegans) to uncover new signaling routes regulating cell death and to study the mechanisms of action of APLs and additional anticancer drugs.