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Open Access 01-12-2023 | Research

Exosomal ACADM sensitizes gemcitabine-resistance through modulating fatty acid metabolism and ferroptosis in pancreatic cancer

Authors: Yuhan Yang, Haitao Gu, Kundong Zhang, Zengya Guo, Xiaofeng Wang, Qingyun Wei, Ling Weng, Xuan Han, Yan Lv, Meng Cao, Peng Cao, Chen Huang, Zhengjun Qiu

Published in: BMC Cancer | Issue 1/2023

Abstract

This study aimed to evaluate the potential of exosomes from cancer cells to predict chemoresistance in pancreatic cancer (PC) and explore the molecular mechanisms through RNA-sequencing and mass spectrometry. We sought to understand the connection between the exosomal Medium-chain acyl-CoA dehydrogenase (ACADM) level and the reaction to gemcitabine in vivo and in patients with PC. We employed loss-of-function, gain-of-function, metabolome mass spectrometry, and xenograft models to investigate the effect of exosomal ACADM in chemoresistance in PC. Our results showed that the molecules involved in lipid metabolism in exosomes vary between PC cells with different gemcitabine sensitivity. Exosomal ACADM (Exo-ACADM) was strongly correlated with gemcitabine sensitivity in vivo, which can be used as a predictor for postoperative gemcitabine chemosensitivity in pancreatic patients. Moreover, ACADM was found to regulate the gemcitabine response by affecting ferroptosis through Glutathione peroxidase 4 (GPX4) and mevalonate pathways. It was also observed that ACADM increased the consumption of unsaturated fatty acids and decreased intracellular lipid peroxides and reactive oxygen species (ROS) levels. In conclusion, this research suggests that Exo-ACADM may be a viable biomarker for predicting the responsiveness of patients to chemotherapy.

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Title: Exosomal ACADM sensitizes gemcitabine-resistance through modulating fatty acid metabolism and ferroptosis in pancreatic cancer
Authors: Yuhan Yang
Haitao Gu
Kundong Zhang
Zengya Guo
Xiaofeng Wang
Qingyun Wei
Ling Weng
Xuan Han
Yan Lv
Meng Cao
Peng Cao
Chen Huang
Zhengjun Qiu
Publication date: 01-12-2023
Publisher: BioMed Central
Published in: BMC Cancer / Issue 1/2023
Electronic ISSN: 1471-2407
DOI: https://doi.org/10.1186/s12885-023-11239-w

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