Tumor-derived interleukin 35 mediates the dissemination of gemcitabine resistance in pancreatic adenocarcinoma
© 2024. The Author(s), under exclusive licence to Springer Nature Limited..
Rapid development of drug resistance after chemotherapy is a major cause of treatment failure in individuals with pancreatic ductal adenocarcinoma (PDAC). In this study, we illustrate that tumor-derived interleukin 35 (IL-35) mediates the accelerated resistance of PDAC to gemcitabine (GEM). We observe that GEM resistance can spread from GEM-resistant PDAC cells to GEM-sensitive cells, and that IL-35 is responsible for the propagation of chemoresistance, which is supported by sequencing and experimental data. Additionally, we discover that GEM-resistant cells have significantly higher levels of IL-35 expression. Mechanistically, aberrantly expressed IL-35 triggers transcriptional activation of SOD2 expression via GP130-STAT1 signaling, scavenging reactive oxygen species (ROS) and leading to GEM resistance. Furthermore, GEM treatment stimulates IL-35 expression through activation of the NF-κB pathway, resulting in acquired chemoresistance. In the mouse model, a neutralizing antibody against IL-35 enhances the tumor suppressive effect of GEM. Collectively, our data suggests that IL-35 is critical in mediating GEM resistance in pancreatic cancer, and therefore could be a valuable therapeutic target in overcoming PDAC chemoresistance.
| Medienart: |
E-Artikel |
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| Erscheinungsjahr: |
2024 |
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| Erschienen: |
2024 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:43 |
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| Enthalten in: |
Oncogene - 43(2024), 11 vom: 08. März, Seite 776-788 |
| Sprache: |
Englisch |
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| Beteiligte Personen: |
Sun, Huizhi [VerfasserIn] |
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| Links: |
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| Themen: |
0W860991D6 |
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| Anmerkungen: |
Date Completed 11.03.2024 Date Revised 11.03.2024 published: Print-Electronic Citation Status MEDLINE |
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| doi: |
10.1038/s41388-024-02938-0 |
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| funding: |
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| Förderinstitution / Projekttitel: |
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| PPN (Katalog-ID): |
NLM367335735 |
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| 520 | |a Rapid development of drug resistance after chemotherapy is a major cause of treatment failure in individuals with pancreatic ductal adenocarcinoma (PDAC). In this study, we illustrate that tumor-derived interleukin 35 (IL-35) mediates the accelerated resistance of PDAC to gemcitabine (GEM). We observe that GEM resistance can spread from GEM-resistant PDAC cells to GEM-sensitive cells, and that IL-35 is responsible for the propagation of chemoresistance, which is supported by sequencing and experimental data. Additionally, we discover that GEM-resistant cells have significantly higher levels of IL-35 expression. Mechanistically, aberrantly expressed IL-35 triggers transcriptional activation of SOD2 expression via GP130-STAT1 signaling, scavenging reactive oxygen species (ROS) and leading to GEM resistance. Furthermore, GEM treatment stimulates IL-35 expression through activation of the NF-κB pathway, resulting in acquired chemoresistance. In the mouse model, a neutralizing antibody against IL-35 enhances the tumor suppressive effect of GEM. Collectively, our data suggests that IL-35 is critical in mediating GEM resistance in pancreatic cancer, and therefore could be a valuable therapeutic target in overcoming PDAC chemoresistance | ||
| 650 | 4 | |a Journal Article | |
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| 650 | 7 | |a Deoxycytidine |2 NLM | |
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| 650 | 7 | |a Antimetabolites, Antineoplastic |2 NLM | |
| 650 | 7 | |a Interleukins |2 NLM | |
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| 700 | 1 | |a Liu, Jing |e verfasserin |4 aut | |
| 700 | 1 | |a Li, Zengxun |e verfasserin |4 aut | |
| 700 | 1 | |a Li, Hui |e verfasserin |4 aut | |
| 700 | 1 | |a Zhao, Tiansuo |e verfasserin |4 aut | |
| 700 | 1 | |a Wang, Xiuchao |e verfasserin |4 aut | |
| 700 | 1 | |a Feng, Yukuan |e verfasserin |4 aut | |
| 700 | 1 | |a Wang, Hongwei |e verfasserin |4 aut | |
| 700 | 1 | |a Gao, Song |e verfasserin |4 aut | |
| 700 | 1 | |a Shi, Lei |e verfasserin |4 aut | |
| 700 | 1 | |a Yang, Shengyu |e verfasserin |4 aut | |
| 700 | 1 | |a Sun, Peiqing |e verfasserin |4 aut | |
| 700 | 1 | |a Chang, Antao |e verfasserin |4 aut | |
| 700 | 1 | |a Hao, Jihui |e verfasserin |4 aut | |
| 700 | 1 | |a Huang, Chongbiao |e verfasserin |4 aut | |
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