Autophagy in Colorectal Cancer: Protective and Curative Effects of Probiotics

Autophagy is a catabolic lysosome-driven process crucial for the maintenance of cellular homeostasis. Any perturbation of this mechanism may dysregulate immune responses and impair bacteria clearance, causing chronic inflammation and favoring the dysbiotic alteration of the microbic flora. Gut dysbiosis is strongly associated with gastrointestinal inflammatory disorders that expose people to the risk of developing colorectal cancer (CRC) compared to healthy people. Recent studies have described the role of host microbiome in cancer initiation and progression, as well as in the modulation of therapeutic responses. The eubiotic state of gut microbiota can be restored by using dietary modulations (e.g., probiotics). Of relevance, in cancer cells there is a crucial interplay between the canonical Wnt pathway, whose regulation is strongly impaired by dysbiosis bacteria, and autophagy: B-Catenin, the key effector of the pathway, inhibits autophagy, while it is degraded by starvation-induced autophagy. Here, we explored the role of autophagy as mechanisms underlying the effects of the microbic flora in the restoration of intestinal homeostasis. We tested the metabolite butyrate on human CRC cell lines, and we examined the fate of the transcription factor B-Catenin. We demonstrated that butyrate-induced autophagy counteracted CRC cell proliferation and migration, promoting the autophagy degradation of B- Catenin. We proposed autophagy as alternative mechanisms for B-Catenin turn over in cancer cells, deficient for the B-Catenin degradation via proteosome. Moreover, we reported that the cell-free supernatant of the probiotic strain Lactiplantibacillus plantarum OC01 contrasted the malignant phenotypes of CRC cells induced by the inflammatory microenvironment. Taken together, we provided the preclinical rationale for the potential therapeutic strategies based on the modulation of microbiota. Manipulating intestinal bacteria may be a significant weapon in clinical practice.