Efecto de la lipoproteína de baja densidad oxidada en la resistencia a Docetaxel y Cabazitaxel inducida por activación de la vía de señalización NF-κB en modelos celulares de cáncer de próstata resistente a castración.
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Date
2022
Authors
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Publisher
Universidad de Concepción
Abstract
El cáncer de próstata avanzado es tratado preferentemente con deprivación de andrógenos (ADT), sin embargo, un gran grupo de pacientes desarrollarán resistencia al tratamiento. El cáncer de próstata resistente a ADT o también conocido como resistente a castración (CPRC) es tratado con Docetaxel, sin embargo, un porcentaje importante de pacientes generará también resistencia a este tratamiento, generando un cáncer de próstata resistente a la castración resistente a Docetaxel. El tratamiento para este tipo de cáncer es el fármaco Cabazitaxel, sin embargo, la efectividad a este medicamento se verá limitada en poco tiempo por la aparición de resistencia en un gran número de pacientes. La vía NF-κB está relacionada con la resistencia a Docetaxel, y se cree que también está relacionada con la resistencia a Cabazitaxel, promoviendo la expresión de ABCB1 y TUBB3. Interesantemente, la lipoproteína de baja densidad oxidada (oxLDL) está aumentada en el plasma de pacientes con CRPC y en otras patologías se ha visto que promueve la activación NF-κB, sin embargo, su función en la generación de resistencia a drogas no ha sido descrita. Hipotetizamos que la activación de las vías de señalización NF-κB p52-p65, por la acción de oxLDL, inducen la resistencia a Docetaxel y Cabazitaxel mediante la sobreexpresión de marcadores de resistencia a la terapia, como MDR1 y TUBB3 en modelos celulares de cáncer de próstata resistente a la castración. Analizamos el efecto de oxLDL sobre la activación de NF-κB p65 y p52 en modelos celulares de CRPC, en la expresión de marcadores de resistencia a taxanos como TUBB3 y MDR1 y su efecto en la sobrevida celular a estas drogas. Los resultados mostraron un aumento en la expresión de NF-κB p65 y p52, un aumento en la expresión de TUBB3 y MDR1, como también un aumento en la supervivencia celular para las líneas tratadas con oxLDL y con los taxanos Docetaxel o Cabazitaxel. También, observamos la sobreexpresión de receptores scavenger para oxLDL en distintos estadios de la enfermedad y que pueden estar contribuyendo a los efectos observados por interacción con oxLDL. Podemos concluir en base a los resultados obtenidos, que la activación NF-κB p52-p65, por acción de oxLDL, inducen la resistencia a Docetaxel y Cabazitaxel mediante la sobreexpresión de MDR1 y TUBB3 en los modelos celulares de cáncer de próstata resistente a la castración estudiados.
Advanced prostate cancer is preferentially treated with androgen deprivation (ADT), however, patients will develop resistance to the treatment. ADT-resistant or also known as castration-resistant prostate cancer (CRPC) is treated with Docetaxel, however, a significant percentage of patients will also develop resistance to this treatment, resulting in Docetaxel-resistant castration-resistant prostate cancer. The treatment for this type of cancer is the drug Cabazitaxel, however, the effectiveness of this drug will be limited in a short time due to the appearance of resistance in a large number of patients. The NF-κB pathway is related to resistance to Docetaxel, and is also believed to be related to resistance to Cabazitaxel, promoting the expression of ABCB1 and TUBB3. Interestingly, oxidized low-density lipoprotein (oxLDL) is increased in the plasma of patients with CRPC and in other pathologies has been seen to promote NF-κB activation, however, its role in the generation of drug resistance has not been described. We hypothesized that activation of NF-κB p52-p65 signaling pathways, by the action of oxLDL, induce resistance to Docetaxel and Cabazitaxel through overexpression of MDR1 and TUBB3 in castration-resistant prostate cancer cell models. We analyzed the effect of oxLDL on NF-κB p65 and p52 activation in CRPC cell models, on the expression of taxane resistance markers such as TUBB3 and MDR1 and their effect on cell survival to these drugs. The results showed increased expression of NF-κB p65 and p52, increased expression of TUBB3 and MDR1, as well as increased cell survival for lines treated with oxLDL, Docetaxel and Cabazitaxel. We also observed overexpression of scavenger receptors for oxLDL at different stages of the disease, which may be contributing to the effects observed by interaction with oxLDL. We can conclude based on the results obtained, that NF-κB p52-p65 activation, by action of oxLDL, induce resistance to Docetaxel and Cabazitaxel through overexpression of MDR1 and TUBB3 in the castration-resistant prostate cancer cell models studied.
Advanced prostate cancer is preferentially treated with androgen deprivation (ADT), however, patients will develop resistance to the treatment. ADT-resistant or also known as castration-resistant prostate cancer (CRPC) is treated with Docetaxel, however, a significant percentage of patients will also develop resistance to this treatment, resulting in Docetaxel-resistant castration-resistant prostate cancer. The treatment for this type of cancer is the drug Cabazitaxel, however, the effectiveness of this drug will be limited in a short time due to the appearance of resistance in a large number of patients. The NF-κB pathway is related to resistance to Docetaxel, and is also believed to be related to resistance to Cabazitaxel, promoting the expression of ABCB1 and TUBB3. Interestingly, oxidized low-density lipoprotein (oxLDL) is increased in the plasma of patients with CRPC and in other pathologies has been seen to promote NF-κB activation, however, its role in the generation of drug resistance has not been described. We hypothesized that activation of NF-κB p52-p65 signaling pathways, by the action of oxLDL, induce resistance to Docetaxel and Cabazitaxel through overexpression of MDR1 and TUBB3 in castration-resistant prostate cancer cell models. We analyzed the effect of oxLDL on NF-κB p65 and p52 activation in CRPC cell models, on the expression of taxane resistance markers such as TUBB3 and MDR1 and their effect on cell survival to these drugs. The results showed increased expression of NF-κB p65 and p52, increased expression of TUBB3 and MDR1, as well as increased cell survival for lines treated with oxLDL, Docetaxel and Cabazitaxel. We also observed overexpression of scavenger receptors for oxLDL at different stages of the disease, which may be contributing to the effects observed by interaction with oxLDL. We can conclude based on the results obtained, that NF-κB p52-p65 activation, by action of oxLDL, induce resistance to Docetaxel and Cabazitaxel through overexpression of MDR1 and TUBB3 in the castration-resistant prostate cancer cell models studied.
Description
Tesis presentada para optar al título de Bioquímico/a.
Keywords
Cáncer, Próstata, Andrógenos, Castración