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.
Highlights
Colorectal cancer (CRC) represents the second cause of cancer-related mortality in developed countries [1]
We demonstrated that CRC cells activate a survival and proliferative loop through BDNF/TrkB signaling [7]; here we investigated the consequences of NT inhibition in SW480 and SW620 cells cultured for 3 hrs with 100 nM K252a
When evaluated the cell death pathway engaged by treated cells, we showed that the double pharmacological treatment significantly increased the apoptotic rate in both cell lines (92.7 for SW480, P < 0.05 and 93.7 for SW620, P < 0.001), whereas the necrotic death remained stable (Fig. 4B)
Summary
CRC represents the second cause of cancer-related mortality in developed countries [1]. In accordance with the UICC TNM classification [2], CRC is categorized into five stages (0–IV), which expand into several subdivisions according to the degree of severity and metastasis. Whereas surgery and chemotherapy are more efficient on low-grade stages, there is no curative treatment for patients with advanced-stage CRC, and mortality remains very high because of the resistance of cancer cells, resulting in treatment avoidance [3]. This aggressiveness could rely on uncontrolled growth factors pathway activation. Neurotrophins (NTs), that is NGF, BDNF, NT3, NT 4/5, initially characterized in the nervous system [4], bind a specific high-affinity, receptor—called Trk (tropomyosin receptor kinase) type A, B and C
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