RESUMEN
El cáncer de próstata presenta una progresión andrógeno-dependiente mediada por el receptor de andrógeno (AR), por lo que el bloqueo androgénico es la terapia estándar para su tratamiento en estado avanzado. Sin embargo, a pesar de una sensibilidad inicial, estos cánceres usualmente evolucionan hacia un estado hormono-resistente. Esta resistencia puede ser debida a una amplificación del gen AR, a sus mutaciones y al aumento en la expresión de proteínas co-activadoras. Igualmente, el receptor AR puede permanecer activo, independientemente de la fijación del ligando por fosforilación de factores de crecimiento y de citosinas. Adicionalmente, hay otras posibles vías independientes del receptor AR, como lo ejemplifica la adquisición del fenotipo neuroendocrino. En esta revisión se examinan tanto los mecanismos moleculares involucrados en la progresión del cáncer de próstata así como la forma en que sus células evaden la apoptosis.
Prostate cancer presents an androgen-dependent growth mediated by the androgen receptor (AR). Androgen pathway blockage is the standard therapy for the treatment of prostate cancer at an advanced stage. In spite of an initial sensitivity, prostate cancer usually becomes refractory to hormone treatment. This resistance can be due to the amplification of the AR gene, AR mutations and the increase in co-activator protein expression. Likewise, growth factors and cytokines can induce AR phosphorylation, independently of ligand fixation. Moreover, there are other AR-independent pathways, such as the acquisition of the neuroendocrine phenotype. In this review, we examine the molecular mechanisms that are involved in the progression of prostate cancer, as well as the ways its cells evade apoptosis.
Asunto(s)
Animales , Humanos , Masculino , Ratones , Andrógenos , Apoptosis , Adenocarcinoma/patología , Neoplasias Hormono-Dependientes/patología , Neoplasias de la Próstata/patología , Adenocarcinoma/tratamiento farmacológico , Antineoplásicos Hormonales/farmacología , Antineoplásicos Hormonales/uso terapéutico , Antineoplásicos/farmacología , Antineoplásicos/uso terapéutico , Proteínas Reguladoras de la Apoptosis/fisiología , Progresión de la Enfermedad , Resistencia a Antineoplásicos , Terapia Molecular Dirigida , Proteínas de Neoplasias/genética , Proteínas de Neoplasias/fisiología , Neoplasias Hormono-Dependientes/tratamiento farmacológico , Células Madre Neoplásicas/efectos de los fármacos , Células Madre Neoplásicas/patología , Neoplasias de la Próstata/tratamiento farmacológico , Receptores Androgénicos/genética , Receptores Androgénicos/fisiología , Transducción de SeñalRESUMEN
We studied the effect of retinoic acid, a potent differentiation inducer, on the proliferation and invasiveness of hormone resistant prostatic cancer cell lines, PC-3 and DU-145. Cellular growth measurement by MTY assay, flow cytometry for cell cycle analysis, Papanicolaou staining for examining the change of morphologic features and in vitro invasion assay using artificial basement membrane, matrigel, were performed under various concentration of all-trans-retinoic acid. Inhibition of cellular proliferation was retinoic acid dose dependent in both cell lines. Decreased S-phase and increased G-1 phase fraction were identified with time dependent manner in both cell lines. Less prominent chromatin and nucleotide, decreased nucleus/cytoplasm ratio were shown in Papanicolaou staining after 7 days culture with 10 uM of retinoic acid. In in vitro invasion assay, PC-3 cells showed decreased netlike formation and penetration though matrigel, and DU-145 cells showed decreased colony formation with 10 uM of retinoic acid. These findings suggest that the retinoic acid could ave the possibility of clinical application in hormone resistant prostatic cancer patients as a new therapeutic modality, differentiation therapy.