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.

中文翻译：

---

Prodigiosin损害自噬体与溶酶体融合，使大肠癌细胞对5-氟尿嘧啶诱导的细胞死亡敏感。

化疗失败是结直肠癌（CRC）患者复发和预后不良的主要原因。抑制自噬是增加化学治疗剂细胞毒性的一种有前途的策略。我们将prodigiosin（一种由各种细菌产生的次级代谢产物）鉴定为一种新型的自噬抑制剂，通过阻止自噬体-溶酶体融合和溶酶体组织蛋白酶的成熟，从而导致LC3B-II和SQSTM的积累来干扰CRC细胞中的自噬通量。在体外，通过prodigiosin抑制自噬使CRC细胞对5-氟尿嘧啶（5-Fu）敏感，联合治疗显着降低了癌细胞的生存能力，部分原因是通过caspase依赖性凋亡引起的。此外，prodigiosin和5-Fu在体内协同抑制CRC异种移植的生长，而没有任何不利影响。结论，