Dual inhibition of BDNF/TrkB and autophagy: a promising therapeutic approach for colorectal cancer

Abstract

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.

Multiplex coherent anti-Stokes Raman scattering microspectroscopy detection of lipid droplets in cancer cells expressing TrkB

“…HEK293 and HEK-Clone2 cells were seeded at a density of 10 4 cells/cm 2 and cultured 2 days before treatment with 75 ng/mL recombinant human BDNF (Peprotech) 44 or with 100 nM of K252a (Alomone) 45 Cells were harvested after 1 h of treatment and proteins were extracted. A dual treatment was performed with BDNF and K252a in order to block the TrkB activation.…”

Development of a Prognostic Model for Colorectal Cancer Based on Four EMT-related Genes

“…However, recent studies have discovered that BDNF and its receptor tropomyosin receptor kinase B (TrkB) were upregulated in a wide range of cancers including CRC (26). Growing evidence showed that BDNF/TrkB pathway was closely involved in CRC proliferation, invasion, migration and poor prognosis (27)(28)(29). Besides, positive results render BDNF/TrkB pathway to be a promising therapeutic target for CRC treatment (27,30).…”

Neurotrophins and their involvement in digestive cancers

“…Colonic tumors express higher BDNF and TrkB transcriptomic and protein levels than non-neoplastic tissues. In addition, the activation of the BDNF/TrkB machinery in CRC cells and tissues and their critical roles in colon tumor growth have previously been demonstrated 15,50,51 . Solid tumors are starved and hypoxic due to the lack of blood vessels, which increases TrkB and sortilin expression, as well as endogenous BDNF production and release.…”