TUMOR METABOLISM AND REGULATION BY MIRNA AS DETERMINANTS OF THE DIFFERENT ANTITUMOR EFFECTS OF MELATONIN (Q3136375)

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Project Q3136375 in Spain
Language Label Description Also known as
English
TUMOR METABOLISM AND REGULATION BY MIRNA AS DETERMINANTS OF THE DIFFERENT ANTITUMOR EFFECTS OF MELATONIN
Project Q3136375 in Spain

    Statements

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    116,160.0 Euro
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    145,200.0 Euro
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    80.0 percent
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    1 January 2015
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    31 March 2018
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    UNIVERSIDAD DE OVIEDO
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    43°21'38.16"N, 5°50'41.64"W
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    33044
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    LA MELATONINA ES UNA INDOLAMINA DE ORIGEN NATURAL QUE EJERCE DISTINTOS EFECTOS ANTITUMORALES EN DISTINTOS TIPOS DE TUMORES, DE FORMA QUE EN LA MAYORIA DE TIPOS TUMORALES INHIBE LA PROLIFERACION CELULAR, MIENTRAS QUE EN ALGUNOS INDUCE MUERTE POR APOPTOSIS, O INCLUSO AUTOFAGIA EN CELULAS MADRE TUMORALES DE GLIOBLASTOMA. PARADOGICAMENTE, MIENTRAS QUE EN LOS TUMORES EN LOS QUE INHIBE LA PROLIFERACION CELULAR DISMINUYE LAS ESPECIES REACTIVAS DE OXIGENO (ROS), EN AQUELLOS EN QUE INDUCE MUERTE LAS AUMENTA, SIENDO ESTE AUMENTO EL RESPONSABLE DEL EFECTO CITOTOXICO. ESTE PUNTO ES LLAMATIVO, YA QUE IN VITRO LA MELATONINA SE HA DEMOSTRADO QUE ES UN POTENTE ANTIOXIDANTE, Y VARIOS DE SUS EFECTOS BIOLOGICOS, ENTRE ELLOS LA INHIBICION DE LA PROLIFERACION CELULAR EN VARIOS TUMORES, SON MEDIADOS POR ESTE EFECTO ANTIOXIDANTE. LA MAYORIA DE ROS EN LA CELULA SE GENERAN DURANTE EL METABOLISMO EN LA MITOCONDRIA. LAS CELULAS TUMORALES PRESENTAN ALTERACIONES EN EL METABOLISMO, DE FORMA QUE OBTIENEN GRAN PARTE DE SU ENERGIA A TRAVES DEL METABOLISMO FERMENTATIVO EN DETRIMENTO DEL METABOLISMO OXIDATIVO. ES LO QUE SE CONOCE COMO GLUCOLISIS AEROBIA O EFECTO WARBURG, CARACTERIZADO ENTRE OTROS, POR AUMENTO DEL TRANSPORTE DE GLUCOSA AL INTERIOR CELULAR Y DE LA PRODUCCION DE LACTADO. POR OTRO LADO, NO TODAS LAS CELULAS TUMORALES PRESENTAN GLUCOLISIS AEROBIA EN LA MISMA MEDIDA, HABIENDO DIFERENCIAS ENTRE LOS DISTINTOS TUMORES. DADO QUE EL EFECTO DIFERENCIAL DE LA MELATONINA TIENE QUE VER CON DISTINTA PRODUCCION DE ROS; QUE ESTAS SE FORMAN SOBRETODO EN EL METABOLISMO OXIDATIVO; Y QUE LAS CELULAS TUMORALES TIENEN DIFERENCIAS EN CUANTO AL TIPO DE METABOLISMO BASAL, NOS PLANTEAMOS QUE EL EFECTO DISTINTO DE LA MELATONINA EN ALGUNOS TUMORES, INDUCIENDO AUMENTO DE ROS Y MUERTE CELULAR, PODRIA SER DEBIDO, NO A UNA ACCION DISTINTA DE LA INDOLAMINA, SINO AL DISTINTO METABOLISMO BASAL DE LAS CELULAS TUMORALES. NUESTRA HIPOTESIS ES QUE LA MELATONINA PODRIA DE ALGUNA FORMA, DIRECTA O INDIRECTA, ESTAR INDUCIENDO UN CAMBIO EN EL METABOLISMO TUMORAL, FORZANDO A CELULAS QUE PRESENTAN EFECTO WARBURG MAS MARCADO, A UTILIZAR EL METABOLISMO OXIDATIVO. SI ESTO OCURRIERA AUMENTARIA EL TRASPORTE DE ELECTRONES Y LAS ROS, QUE PODRIAN SER NOCIVAS PARA LA CELULA. ADEMAS DE INTENTAR CONFIRMAR DICHA HIPOTESIS, EN LA PROPUESTA QUE PRESENTAMOS TRATAREMOS DE DESCIFRAR CUALES SON LAS "PECULIARIDADES" EN TERMINOS BIOLOGICOS DE LAS CELULAS TUMORALES SENSIBLES A ESTE EFECTO CITOTOXICO. LOS FACTORES DE TRANSCRIPCION QUE REGULAN DE FORMA CLAVE ESTE CAMBIO DEL METABOLISMO EN LAS CELUAS TUMORALES (HIF 1 ALFA O MTOR), AL IGUAL QUE VARIAS ENZIMAS IMPLICADAS EN EL TRANSPORTE DE GLUCOSA, LA GLUCOLISIS Y EL CICLO DE KREBS, ADEMAS DE REGULARSE TRANSCRIPCIONALMENTE, LO HACEN POSTTRASCRIPCIONALMENTE A TRAVES DE VARIOS MIRNA. LA EXPRESION DE ESTOS, TAMBIEN ES DISTINTA EN LOS DISTINTOS TUMORES, Y YA HAY PUBLICACIONES INDICANDO QUE LA MELATONINA REGULA MIRNAS. POR TANTO, ESTUDIAREMOS EN UN PANEL DE LINEAS CELULARES PERTENECIENTES A LOS DOS GRUPOS DE TUMORES EN CUANTO A EFECTO DE LA MELATONINA (INHIBICION DE PROLIFERACION VS INDUCCION DE MUERTE), EL TIPO DE METABOLISMO BASAL Y LOS EFECTOS DE LA MELATONINA SOBRE ESTE; Y LA EXPRESION DE MIRNAS RELACIONANDOLOS CON LOS CAMBIOS METABOLICOS HALLADOS Y SU POSIBLE REGULACION POR LA MELATONINA. FINALMENTE TRATAREMOS DE CONFIRMAR LOS RESULTADOS ENCONTRADOS EN CELUALS EXTRAIDAS DE TUMORES DE PACIENTES: GLIOBLASTOMA (EFECTO CITOSTATICO) Y LEUCEMIA MIELOIDE AGUDA (CITOTOXICIDAD). (Spanish)
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    MELATONIN IS AN INDOLAMINE OF NATURAL ORIGIN THAT EXERTS DIFFERENT ANTITUMOR EFFECTS ON DIFFERENT TYPES OF TUMORS, SO THAT IN MOST TUMOR TYPES IT INHIBITS CELL PROLIFERATION, WHILE IN SOME IT INDUCES DEATH FROM APOPTOSIS, OR EVEN AUTOPHAGIA IN TUMOR STEM CELLS OF GLIOBLASTOMA. PARADOXICALLY, WHILE IN THE TUMORS IN WHICH IT INHIBITS CELL PROLIFERATION DECREASES THE REACTIVE SPECIES OF OXYGEN (ROS), IN THOSE IN WHICH IT INDUCES DEATH INCREASES THEM, THIS INCREASE BEING RESPONSIBLE FOR THE CYTOTOXIC EFFECT. THIS POINT IS STRIKING, SINCE IN VITRO MELATONIN HAS BEEN SHOWN TO BE A POTENT ANTIOXIDANT, AND SEVERAL OF ITS BIOLOGICAL EFFECTS, INCLUDING INHIBITION OF CELL PROLIFERATION IN SEVERAL TUMORS, ARE MEDIATED BY THIS ANTIOXIDANT EFFECT. MOST ROS IN THE CELL ARE GENERATED DURING METABOLISM IN MITOCHONDRIA. TUMOR CELLS HAVE ALTERATIONS IN METABOLISM, SO THEY OBTAIN MUCH OF THEIR ENERGY THROUGH FERMENTATIVE METABOLISM TO THE DETRIMENT OF OXIDATIVE METABOLISM. IT IS KNOWN AS AEROBIC GLYCOLYSIS OR WARBURG EFFECT, CHARACTERISED AMONG OTHERS BY INCREASED TRANSPORT OF GLUCOSE INTO THE CELL AND LACTATION PRODUCTION. ON THE OTHER HAND, NOT ALL TUMOR CELLS PRESENT AEROBIC GLYCOLYSIS TO THE SAME EXTENT, THERE ARE DIFFERENCES BETWEEN THE DIFFERENT TUMORS. SINCE THE DIFFERENTIAL EFFECT OF MELATONIN HAS TO DO WITH DIFFERENT PRODUCTION OF ROS; WHEREAS THESE ARE MAINLY FORMED IN OXIDATIVE METABOLISM; AND THAT TUMOR CELLS HAVE DIFFERENCES IN THE TYPE OF BASAL METABOLISM, WE PROPOSE THAT THE DIFFERENT EFFECT OF MELATONIN IN SOME TUMORS, INDUCING INCREASED ROS AND CELL DEATH, COULD BE DUE NOT TO AN ACTION OTHER THAN INDOLAMINE, BUT TO THE DIFFERENT BASAL METABOLISM OF TUMOR CELLS. OUR HYPOTHESIS IS THAT MELATONIN MIGHT IN SOME WAY, DIRECTLY OR INDIRECTLY, BE INDUCING A CHANGE IN TUMOR METABOLISM, FORCING CELLS WITH A MORE MARKED WARBURG EFFECT TO USE OXIDATIVE METABOLISM. IF THIS WERE TO HAPPEN, IT WOULD INCREASE THE TRANSPORT OF ELECTRONS AND ROS, WHICH COULD BE HARMFUL TO THE CELL. IN ADDITION TO TRYING TO CONFIRM THIS HYPOTHESIS, IN OUR PROPOSAL WE WILL TRY TO DECIPHER WHAT ARE THE “PECULIARITIES” IN BIOLOGICAL TERMS OF TUMOR CELLS SENSITIVE TO THIS CYTOTOXIC EFFECT. THE TRANSCRIPTION FACTORS THAT KEYLY REGULATE THIS CHANGE OF METABOLISM IN TUMOR CELUAS (HIF 1 ALPHA OR MTOR), AS WELL AS SEVERAL ENZYMES INVOLVED IN GLUCOSE TRANSPORT, GLYCOLYSIS AND THE KREBS CYCLE, IN ADDITION TO BEING TRANSCRIBED, DO SO POSTTRASCRIPCIONELY THROUGH SEVERAL MIRNA. THE EXPRESSION OF THESE IS ALSO DIFFERENT IN DIFFERENT TUMORS, AND THERE ARE ALREADY PUBLICATIONS INDICATING THAT MELATONIN REGULATES MIRNAS. THEREFORE, WE WILL STUDY IN A PANEL OF CELL LINES BELONGING TO THE TWO GROUPS OF TUMORS IN TERMS OF EFFECT OF MELATONIN (INHIBITION OF PROLIFERATION VS INDUCTION OF DEATH), THE TYPE OF BASAL METABOLISM AND THE EFFECTS OF MELATONIN ON IT; AND THE EXPRESSION OF MIRNAS RELATING THEM TO THE METABOLIC CHANGES FOUND AND THEIR POSSIBLE REGULATION BY MELATONIN. FINALLY, WE WILL TRY TO CONFIRM THE RESULTS FOUND IN CELUALS EXTRACTED FROM PATIENT TUMORS: GLIOBLASTOMA (CYTOSTATIC EFFECT) AND ACUTE MYELOID LEUKEMIA (CYTOTOXICITY). (English)
    12 October 2021
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    Oviedo
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    Identifiers

    SAF2014-58468-R
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