RESUMEN
Colorectal cancer (CRC) is the most common digestive cancer in the Western world. Despite effective therapies, resistance and/or recurrence frequently occur. The present study investigated the impact of two survival pathways-neurotrophic factors (TrkB/BDNF) and autophagy-on cell fate and tumour evolution. In vitro studies were performed on two CRC cell lines, SW480 (primary tumour) and SW620 (lymph node invasion), which were also used for subcutaneous xenografts on a nude mouse model. In addition, the presence of neurotrophic factors (NTs) and autophagy markers were assessed in tissue samples representative of different stages. On the basis of our previous study (which demonstrated that TrkB overexpression is associated with prosurvival signaling in CRC cells), we pharmacologically inhibited NTs pathways with K252a. As expected, an inactivation of the PI3K/AKT pathway was observed and CRC cells initiated autophagy. Conversely, blocking the autophagic flux with chloroquine or with ATG5-siRNA overactivated TrkB/BDNF signaling. In vitro, dual inhibition improved the effectiveness of single treatment by significantly reducing metabolic activity and enhancing apoptotic cell death. These findings were accentuated in vivo, in which dual inhibition induced a spectacular reduction in tumour volume following long-term treatment (21 days for K252a and 12 days for CQ). Finally, significant amounts of phospho-TrkB and LC3II were found in the patients' tissues, highlighting their relevance in CRC tumour biology. Taken together, our results show that targeting NTs and autophagy pathways potentially constitutes a new therapeutic approach for CRC.
Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/farmacología , Autofagia/efectos de los fármacos , Factor Neurotrófico Derivado del Encéfalo/antagonistas & inhibidores , Neoplasias Colorrectales/tratamiento farmacológico , Receptor trkB/antagonistas & inhibidores , Ensayos Antitumor por Modelo de Xenoinjerto , Anciano , Anciano de 80 o más Años , Animales , Proteína 5 Relacionada con la Autofagia/genética , Proteína 5 Relacionada con la Autofagia/metabolismo , Factor Neurotrófico Derivado del Encéfalo/metabolismo , Carbazoles/administración & dosificación , Línea Celular Tumoral , Cloroquina/administración & dosificación , Neoplasias Colorrectales/genética , Neoplasias Colorrectales/metabolismo , Inhibidores Enzimáticos/administración & dosificación , Femenino , Humanos , Alcaloides Indólicos/administración & dosificación , Masculino , Ratones Endogámicos , Ratones Desnudos , Interferencia de ARN , Receptor trkB/metabolismo , Estudios Retrospectivos , Carga Tumoral/efectos de los fármacosRESUMEN
Previous studies have reported the association between brain-derived neurotrophic factor (BDNF) and tumor development in numerous cancers. However, the accurate implication of the two specific ligands of tropomyosin kinase B receptor, BDNF and neurotrophic factor 4 (NT4/5), has not been studied in colorectal cancer (CRC) patients. The present study investigated the significance of serum BDNF and the NT4/5 in association with the intake of psychoactive drugs in CRC patients. Soluble BDNF and NT4 in the serum were assessed by ELISA. Although no correlation of BDNF and NT4 with the CRC stage was identified, a positive correlation was found between NT4 and the intake of psychoactive drugs (P=0.0457). For BDNF, a correlation was found in particular with the intake of benzodiazepine (P=0.0221). As BDNF and NT4/5 are implicated in the response of psychoactive treatments applied to manage depression, which frequently occurs in cancer patients, they cannot be used as prognostic or diagnostic markers for CRC in these patients. However, high expression of BDNF and NT4 was significantly associated with better survival. Therefore, these NTs may be used as markers for monitoring depression or predicting survival in CRC patients.
