AKR1B1 promotes pancreatic cancer metastasis by regulating lysosome-guided exosome secretion
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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.
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AKR1B1 promotes pancreatic cancer metastasis by regulating lysosome-guided exosome secretion
)
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.
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Acknowledgements
This study was supported by grants from the National Natural Science Foundation (No. 81702419), the National Science Fund for Distinguished Young Scholars (No. 82000497), the Key Research and Development Plan of Jiangsu Province (Nos. BE2019692 and BE2020668), the Natural Science Foundation of Jiangsu Province (Nos. BK20211105 and BK20200965), the Postdoctoral Science Foundation of China (No. 2019M661909), the Social Development Foundation of Nantong City (Nos. MS22020005 and MSZ20076), and the Postgraduate Research & Practice Innovation Program of Jiangsu Province (Nos. KYCX20_2681, KYCX20_2673, and KYCX21_3112).
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