RESUMO
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.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Autofagia/efeitos dos fármacos , Fator Neurotrófico Derivado do Encéfalo/antagonistas & inibidores , Neoplasias Colorretais/tratamento farmacológico , Receptor trkB/antagonistas & inibidores , Ensaios Antitumorais Modelo de Xenoenxerto , Idoso , Idoso de 80 Anos ou mais , Animais , Proteína 5 Relacionada à Autofagia/genética , Proteína 5 Relacionada à Autofagia/metabolismo , Fator Neurotrófico Derivado do Encéfalo/metabolismo , Carbazóis/administração & dosagem , Linhagem Celular Tumoral , Cloroquina/administração & dosagem , Neoplasias Colorretais/genética , Neoplasias Colorretais/metabolismo , Inibidores Enzimáticos/administração & dosagem , Feminino , Humanos , Alcaloides Indólicos/administração & dosagem , Masculino , Camundongos Endogâmicos , Camundongos Nus , Interferência de RNA , Receptor trkB/metabolismo , Estudos Retrospectivos , Carga Tumoral/efeitos dos fármacosRESUMO
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.