Exosomal ACADM sensitizes gemcitabine-resistance through modulating fatty acid metabolism and ferroptosis in pancreatic cancer
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...
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BMC
2023-08-01
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| Series: | BMC Cancer |
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| Online Access: | https://doi.org/10.1186/s12885-023-11239-w |
| _version_ | 1827710525679599616 |
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| author | 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 |
| author_facet | 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 |
| author_sort | Yuhan Yang |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-03-10T17:40:25Z |
| format | Article |
| id | doaj.art-04dc96e64da44d898d7348d60f78c3f0 |
| institution | Directory Open Access Journal |
| issn | 1471-2407 |
| language | English |
| last_indexed | 2024-03-10T17:40:25Z |
| publishDate | 2023-08-01 |
| publisher | BMC |
| record_format | Article |
| series | BMC Cancer |
| spelling | doaj.art-04dc96e64da44d898d7348d60f78c3f02023-11-20T09:42:56ZengBMCBMC Cancer1471-24072023-08-0123111410.1186/s12885-023-11239-wExosomal ACADM sensitizes gemcitabine-resistance through modulating fatty acid metabolism and ferroptosis in pancreatic cancerYuhan Yang0Haitao Gu1Kundong Zhang2Zengya Guo3Xiaofeng Wang4Qingyun Wei5Ling Weng6Xuan Han7Yan Lv8Meng Cao9Peng Cao10Chen Huang11Zhengjun Qiu12Department of General Surgery, Shanghai General Hospital, Shanghai Jiao Tong University School of MedicineDepartment of General Surgery, Shanghai General Hospital, Shanghai Jiao Tong University School of MedicineDepartment of General Surgery, Shanghai General Hospital, Shanghai Jiao Tong University School of MedicineDepartment of General Surgery, Shanghai General Hospital, Shanghai Jiao Tong University School of MedicineDepartment of Thoracic Surgery, Ruijin Hospital, Shanghai Jiao Tong University School of MedicineAffiliated Hospital of Integrated Traditional Chinese and Western Medicine, Nanjing University of Chinese MedicineAffiliated Hospital of Integrated Traditional Chinese and Western Medicine, Nanjing University of Chinese MedicineAffiliated Hospital of Integrated Traditional Chinese and Western Medicine, Nanjing University of Chinese MedicineAffiliated Hospital of Integrated Traditional Chinese and Western Medicine, Nanjing University of Chinese MedicineAffiliated Hospital of Integrated Traditional Chinese and Western Medicine, Nanjing University of Chinese MedicineAffiliated Hospital of Integrated Traditional Chinese and Western Medicine, Nanjing University of Chinese MedicineDepartment of General Surgery, Shanghai General Hospital, Shanghai Jiao Tong University School of MedicineDepartment of General Surgery, Shanghai General Hospital, Shanghai Jiao Tong University School of MedicineAbstract 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.https://doi.org/10.1186/s12885-023-11239-wExosomesLipid metabolismFerroptosisPancreatic cancerBiomarkerGemcitabine |
| spellingShingle | 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 Exosomal ACADM sensitizes gemcitabine-resistance through modulating fatty acid metabolism and ferroptosis in pancreatic cancer BMC Cancer Exosomes Lipid metabolism Ferroptosis Pancreatic cancer Biomarker Gemcitabine |
| title | Exosomal ACADM sensitizes gemcitabine-resistance through modulating fatty acid metabolism and ferroptosis in pancreatic cancer |
| title_full | Exosomal ACADM sensitizes gemcitabine-resistance through modulating fatty acid metabolism and ferroptosis in pancreatic cancer |
| title_fullStr | Exosomal ACADM sensitizes gemcitabine-resistance through modulating fatty acid metabolism and ferroptosis in pancreatic cancer |
| title_full_unstemmed | Exosomal ACADM sensitizes gemcitabine-resistance through modulating fatty acid metabolism and ferroptosis in pancreatic cancer |
| title_short | Exosomal ACADM sensitizes gemcitabine-resistance through modulating fatty acid metabolism and ferroptosis in pancreatic cancer |
| title_sort | exosomal acadm sensitizes gemcitabine resistance through modulating fatty acid metabolism and ferroptosis in pancreatic cancer |
| topic | Exosomes Lipid metabolism Ferroptosis Pancreatic cancer Biomarker Gemcitabine |
| url | https://doi.org/10.1186/s12885-023-11239-w |
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