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Research Article

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

Jie Ji1,§, Dandan Jin2,§, Minxue Xu1,§, Yujie Jiao3, Yue Wu1, Tong Wu1, Renjie Lin1, Wenjie Zheng4, Zhaoxiu Liu1, Feng Jiang1, Yihui Fan5, Mingbing Xiao1,4( )
Department of Gastroenterology, Affiliated Hospital and Medical School of Nantong University, Nantong 226001, China
Third People’s Hospital Affiliated to Nantong University, Nantong 226001, China
Department of Gastroenterology, Second People’s Hospital of Changshu, Changshu 215500, China
Research Center of Clinical Medicine, Affiliated Hospital of Nantong University, Nantong 226001, China
Department of Pathogenic Biology, School of Medicine, Nantong University, Nantong 226001, China

§ Jie Ji, Dandan Jin, and Minxue Xu contributed equally to this work.

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Abstract

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.

Graphical Abstract

Aldo-keto reductase family 1 member B1 (AKR1B1) accelerates liver metastasis in pancreaticcancer by promoting exosome secretion. This is because AKR1B1 can enhance lysosomal functionand multivesicular bodies (MVBs) degradation in lysosomes by increasing levels of transcriptionfactor EB (TFEB) and RAB7A.

Keywords

aldo-keto reductase family 1 member B1 (AKR1B1)pancreatic cancerexosome secretionlysosomeEpalrestat

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Nano Research
Volume 15 Issue 6,
June 2022
Pages 5279-5294
DOI: 10.1007/s12274-022-4167-z

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Cite this article:
Ji J, Jin D, Xu M, et al. AKR1B1 promotes pancreatic cancer metastasis by regulating lysosome-guided exosome secretion. Nano Research, 2022, 15(6): 5279-5294. https://doi.org/10.1007/s12274-022-4167-z
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Received: 09 December 2021
Revised: 10 January 2022
Accepted: 13 January 2022
Published: 04 March 2022
© Tsinghua University Press 2022