Prodigiosin impairs autophagosome-lysosome fusion that sensitizes colorectal cancer cells to 5-fluorouracil-induced cell death

Chemotherapy failure is a major cause of recurrence and poor prognosis in colorectal Cancer (CRC) patients. Inhibition of Autophagy is a promising strategy to augment the cytotoxicity of chemotherapeutic agents. We identified prodigiosin, a secondary metabolite produced by various bacteria, as a novel Autophagy Inhibitor that interfered with the autophagic flux in CRC cells by blocking autophagosome-lysosome fusion and lysosomal Cathepsin maturation, resulting in the accumulation of LC3B-II and SQSTM. Suppression of Autophagy by prodigiosin sensitized the CRC cells to 5-fluorouracil (5-Fu) in vitro, and the combination treatment markedly reduced Cancer cell viability partly via caspase-dependent Apoptosis. Furthermore, prodigiosin and 5-Fu synergistically inhibited CRC xenograft growth in vivo without any adverse effects. In conclusion, prodigiosin inhibits late stage Autophagy and sensitizes tumor cells to 5-Fu, indicating its therapeutic potential in CRC.