RESUMEN
PTPL1 is a non-receptor protein tyrosine phosphatase involved in apoptosis regulation, although controversial findings have been reported in different cancer types. We report here a proapoptotic role for PTPL1 in PC3 and LNCaP prostate cancer cells, as its absence induces apoptosis resistance upon treatment with different drugs. In PC3 cells, PTPL1 silencing by small interfering RNA influences the expression levels of Bcl-xL and Mcl-1(S) proteins as well as final events in the apoptotic process such as activation of caspases and caspase-mediated cleavage of proteins like Mcl-1 or poly (ADP-ribose) polymerase. We have identified PKCδ as an intermediary of PTPL1-mediated apoptotic signalling and that phosphorylation status of NF-κB and IκBα is influenced by PTPL1 and PKCδ. Furthermore, the loss of PTPL1 and PKCδ expression in poorly differentiated, more aggressive human prostate cancers also indicate that their absence could be related to apoptosis resistance and tumour progression.
Asunto(s)
Regulación Neoplásica de la Expresión Génica , Neoplasias de la Próstata/genética , Proteína Quinasa C-delta/genética , Proteína Tirosina Fosfatasa no Receptora Tipo 13/genética , Transducción de Señal/genética , Apoptosis , Diferenciación Celular , Línea Celular Tumoral , Proliferación Celular , Humanos , Quinasa I-kappa B/genética , Quinasa I-kappa B/metabolismo , Masculino , Proteína 1 de la Secuencia de Leucemia de Células Mieloides , FN-kappa B/genética , FN-kappa B/metabolismo , Neoplasias de la Próstata/metabolismo , Proteína Quinasa C-delta/antagonistas & inhibidores , Proteína Quinasa C-delta/metabolismo , Proteína Tirosina Fosfatasa no Receptora Tipo 13/antagonistas & inhibidores , Proteína Tirosina Fosfatasa no Receptora Tipo 13/metabolismo , Proteínas Proto-Oncogénicas c-bcl-2/genética , Proteínas Proto-Oncogénicas c-bcl-2/metabolismo , ARN Interferente Pequeño , Proteína bcl-X/genética , Proteína bcl-X/metabolismoRESUMEN
We studied two pedigrees with a mutation at the nucleotide 3243 of mitochondrial DNA (mtDNA). The proband from the first pedigree had clinically defined MELAS plus maternally transmitted insulin-dependent diabetes mellitus (IDDM). The propositus of the other pedigree had exercise intolerance, lactic acidosis and ragged-red fibers (RRF). In the first pedigree, both the mother and the sister's proband harbored the point mutation in their muscle. The mother had 40% of mutant mitochondrial genomes and the sister 70%. In the second pedigree, the mutation was present in both muscle and blood from the proband as well as in blood from all other members studied. Proportion of mutant mtDNA was 90% in muscle and ranged from 40% to 90% in blood.