Neobractatin and Trametinib Synergistically Induce Apoptosis and Gasdermin E‐Dependent Pyroptosis in Pancreatic Cancer Cells
ABSTRACT Mutations in mitogen‐activated protein kinase kinase (MEK) are prevalent in pancreatic ductal adenocarcinoma (PDAC), but many MEK inhibitors inadvertently activate protein kinase B (AKT). We propose a promising PDAC treatment strategy by combining the MEK inhibitor trametinib with neobracta...
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Wiley
2025-07-01
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| Online Access: | https://doi.org/10.1002/mco2.70250 |
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| author | Jiaqi Tan Ziyi Bao Kai Qin Liujing Zhu Changwu Zheng Jiabin Jin Li Zhang Hongxi Xu |
| author_facet | Jiaqi Tan Ziyi Bao Kai Qin Liujing Zhu Changwu Zheng Jiabin Jin Li Zhang Hongxi Xu |
| author_sort | Jiaqi Tan |
| collection | DOAJ |
| description | ABSTRACT Mutations in mitogen‐activated protein kinase kinase (MEK) are prevalent in pancreatic ductal adenocarcinoma (PDAC), but many MEK inhibitors inadvertently activate protein kinase B (AKT). We propose a promising PDAC treatment strategy by combining the MEK inhibitor trametinib with neobractatin (NBT), a natural compound from Garcinia bracteata. Our results demonstrated that this combination significantly impeded cell growth by inducing gasdermin E (GSDME)‐mediated pyroptosis and apoptosis. GSDME, overexpressed in PDAC tissues and correlated with histological differentiation, underscores the role of pyroptosis in PDAC. RNA‐seq results indicated that the phosphoinositide 3‐kinase/protein kinase B (PI3K/AKT) pathway was the primary target of the combination treatment. Mechanistic studies revealed the combination effectively reduced both total and phosphorylated AKT levels, thereby inhibiting protein kinase B/IκB kinase (AKT/IKK) and protein kinase B/mammalian target of rapamycin (AKT/mTOR) signaling pathways. Additionally, the combination disrupted mTOR complex 2 (mTORC2), preventing the trametinib‐induced AKT activation. MicroRNA sequencing analysis indicated that the combination reduced AKT levels by upregulated miR‐149‐5p. Further research demonstrated that the combination increased intracellular reactive oxygen species (ROS), while N‐acetylcysteine (NAC, a ROS scavenger) reversed the cell growth inhibition and AKT suppression. In vivo, the combination significantly inhibited tumor growth by inducing pyroptosis and apoptosis, outperforming gemcitabine. Our findings provide novel insights into the potential of combining NBT and trametinib to induce pyroptosis and apoptosis through the ROS/AKT/GSDME axis, offering a theoretical basis for future PDAC treatment. |
| format | Article |
| id | doaj-art-89e01ac2c6f941579914265986162e8f |
| institution | Kabale University |
| issn | 2688-2663 |
| language | English |
| publishDate | 2025-07-01 |
| publisher | Wiley |
| record_format | Article |
| series | MedComm |
| spelling | doaj-art-89e01ac2c6f941579914265986162e8f2025-08-20T03:50:49ZengWileyMedComm2688-26632025-07-0167n/an/a10.1002/mco2.70250Neobractatin and Trametinib Synergistically Induce Apoptosis and Gasdermin E‐Dependent Pyroptosis in Pancreatic Cancer CellsJiaqi Tan0Ziyi Bao1Kai Qin2Liujing Zhu3Changwu Zheng4Jiabin Jin5Li Zhang6Hongxi Xu7School of PharmacyShanghai University of Traditional Chinese MedicineShanghaiChinaSchool of PharmacyShanghai University of Traditional Chinese MedicineShanghaiChinaDepartment of General SurgeryPancreatic Disease CenterRuijin Hospital, Shanghai Jiao Tong University School of MedicineShanghaiChinaSchool of PharmacyShanghai University of Traditional Chinese MedicineShanghaiChinaSchool of PharmacyShanghai University of Traditional Chinese MedicineShanghaiChinaDepartment of General SurgeryPancreatic Disease CenterRuijin Hospital, Shanghai Jiao Tong University School of MedicineShanghaiChinaSchool of PharmacyShanghai University of Traditional Chinese MedicineShanghaiChinaShuguang Hospital, Shanghai University of Traditional Chinese MedicineShanghaiChinaABSTRACT Mutations in mitogen‐activated protein kinase kinase (MEK) are prevalent in pancreatic ductal adenocarcinoma (PDAC), but many MEK inhibitors inadvertently activate protein kinase B (AKT). We propose a promising PDAC treatment strategy by combining the MEK inhibitor trametinib with neobractatin (NBT), a natural compound from Garcinia bracteata. Our results demonstrated that this combination significantly impeded cell growth by inducing gasdermin E (GSDME)‐mediated pyroptosis and apoptosis. GSDME, overexpressed in PDAC tissues and correlated with histological differentiation, underscores the role of pyroptosis in PDAC. RNA‐seq results indicated that the phosphoinositide 3‐kinase/protein kinase B (PI3K/AKT) pathway was the primary target of the combination treatment. Mechanistic studies revealed the combination effectively reduced both total and phosphorylated AKT levels, thereby inhibiting protein kinase B/IκB kinase (AKT/IKK) and protein kinase B/mammalian target of rapamycin (AKT/mTOR) signaling pathways. Additionally, the combination disrupted mTOR complex 2 (mTORC2), preventing the trametinib‐induced AKT activation. MicroRNA sequencing analysis indicated that the combination reduced AKT levels by upregulated miR‐149‐5p. Further research demonstrated that the combination increased intracellular reactive oxygen species (ROS), while N‐acetylcysteine (NAC, a ROS scavenger) reversed the cell growth inhibition and AKT suppression. In vivo, the combination significantly inhibited tumor growth by inducing pyroptosis and apoptosis, outperforming gemcitabine. Our findings provide novel insights into the potential of combining NBT and trametinib to induce pyroptosis and apoptosis through the ROS/AKT/GSDME axis, offering a theoretical basis for future PDAC treatment.https://doi.org/10.1002/mco2.70250AKTgasdermin Epancreatic ductal adenocarcinomapyroptosisROS |
| spellingShingle | Jiaqi Tan Ziyi Bao Kai Qin Liujing Zhu Changwu Zheng Jiabin Jin Li Zhang Hongxi Xu Neobractatin and Trametinib Synergistically Induce Apoptosis and Gasdermin E‐Dependent Pyroptosis in Pancreatic Cancer Cells MedComm AKT gasdermin E pancreatic ductal adenocarcinoma pyroptosis ROS |
| title | Neobractatin and Trametinib Synergistically Induce Apoptosis and Gasdermin E‐Dependent Pyroptosis in Pancreatic Cancer Cells |
| title_full | Neobractatin and Trametinib Synergistically Induce Apoptosis and Gasdermin E‐Dependent Pyroptosis in Pancreatic Cancer Cells |
| title_fullStr | Neobractatin and Trametinib Synergistically Induce Apoptosis and Gasdermin E‐Dependent Pyroptosis in Pancreatic Cancer Cells |
| title_full_unstemmed | Neobractatin and Trametinib Synergistically Induce Apoptosis and Gasdermin E‐Dependent Pyroptosis in Pancreatic Cancer Cells |
| title_short | Neobractatin and Trametinib Synergistically Induce Apoptosis and Gasdermin E‐Dependent Pyroptosis in Pancreatic Cancer Cells |
| title_sort | neobractatin and trametinib synergistically induce apoptosis and gasdermin e dependent pyroptosis in pancreatic cancer cells |
| topic | AKT gasdermin E pancreatic ductal adenocarcinoma pyroptosis ROS |
| url | https://doi.org/10.1002/mco2.70250 |
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