Journal
CANCER LETTERS
Volume 481, Issue -, Pages 15-23Publisher
ELSEVIER IRELAND LTD
DOI: 10.1016/j.canlet.2020.03.010
Keywords
Prodigiosin; Colorectal cancer; Autophagy flux; Chemotherapy; Apoptosis
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Funding
- National Natural Science Foundation of China [81871905, 81700486]
- Guangzhou Science, Technology and Innovation Commission [201906010052]
- Fundamental Research Funds for the Central Universities [2017Q113]
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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.
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