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.

The biogenesis and secretion of exosomes and multivesicular bodies(MVBs):Intercellular shuttles and implications in human diseases

Exosomes carry and transmit signaling molecules used for intercellular communication.The generation and secretion of exosomes is a multistep interlocking process that allows simultaneous control of multiple regulatory sites.Protein molecules,mainly RAB GTPases,cytoskeletal proteins and soluble N-ethylmaleimide-sensitive fusion attachment protein receptor(SNARE),are specifically regulated in response to pathological conditions such as altered cellular microenvironment,stimulation by pathogenic factors,or gene mutation.This interferes with the smooth functioning of endocytosis,translocation,degradation,docking and fusion processes,leading to changes in the secretion of exosomes.Large numbers of secreted exosomes are disseminated by the flow of body fluids and absorbed by the recipient cells.By transmitting characteristic functional proteins and genetic information produced under disease conditions,exosomes can change the physiological state of the recipient cells and their microenvironment.The microenvironment,in turn,affects the occurrence and development of disease.Therefore,this review will discuss the mechanism by which exosome secretion is regulated in cells following the formation of mature secretory multivesicular bodies(MVBs).The overall aim is to find ways to eliminate disease-derived exosomes at their source,thereby providing an important new basis for the clinical treatment of disease.