AKR1B1 promotes pancreatic cancer metastasis by regulating lysosome-guided exosome secretion

Pancreatic cancer is one of the most lethal neoplasms with high metastatic potential and is resistant to almost all current therapies. Epalrestat is an aldo-keto reductase family 1 member B1 (AKR1B1) inhibitor for the treatment of diabetic neuropathy, but its potential application in cancer treatment and the underlying mechanism are largely unknown. Here, we found that AKR1B1 is upregulated in pancreatic cancer and is positively associated with metastasis. Upregulated AKR1B1 promoted exosome secretion, accelerating cell migration in pancreatic cancer cells. Further analysis indicated that AKR1B1 negatively regulated lysosomal function and multivesicular body (MVB) degradation in lysosomes. However, AKR1B1 had a minimal role in the generation of MVBs. Transcription factor EB (TFEB) and MVB-expressed RAB7A were two molecular targets that are negatively regulated by AKR1B1. These results uncovered a critical role for AKR1B1 in the regulation of lysosomal function and exosome secretion. Pharmacological targeting of AKR1B1 by clinically used medicines, such as Epalrestat, might represent an efficient way to inhibit pancreatic growth and metastasis.