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Ginkgolide B regulates the proliferation, migration, apoptosis, and epithelialmesenchymal transition of liver cancer cells through the PERK/ATF4/CHOP pathway
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Abstract:
[Abstract] Objective: To investigate the effects of ginkgolide B (GKB) on the proliferation, migration, apoptosis, and epithelialmesenchymal transition (EMT) of liver cancer cells by regulating the protein kinase R-like endoplasmic reticulum kinase (PERK)/ activating transcription factor 4 (ATF4)/C/EBP homologous protein (CHOP) signaling pathway. Methods: Human liver cancer cells MHCC-97H were randomly assigned into the control group, the GKB group, the GSK2656157 (PERK inhibitors) group, and the GKB + GSK2656157 group. After intervention with GKB and PERK inhibitors GSK2656157 on different groups, MTT assay and EdU staining were used to detect the proliferation activity and proliferation rate of cells in each group. Scratch assay and flow cytometry were used to detect the migration and apoptosis of cells in each group, respectively. Western blotting (WB) was used to detect the expression levels of EMT and PERK/ATF4/CHOP signaling pathway related proteins in each group. The MHCC-97H nude mouse transplant tumor model was constructed, and the tumor volumes of each group were measured after grouping and drug intervention. Immunohistochemistry and TUNEL staining were used to detect the proliferation and apoptosis of tumor cells in each group. In addition, WB was used to detect the expression levels of EMT and PERK/ATF4/CHOP signaling pathway related proteins in transplant tumor tissues of each group. Results: Compared with those in the control group, the cell activity, proliferation rate, migration rate, tumor volume, Ki-67 positive cell ratio, and relative expressions of MMP2, N-cadherin, and MMP9 proteins decreased significantly in the GKB group (all P < 0.05), while the apoptosis rate, TUNEL positive cell ratio, and the expressions of p-PERK/PERK, E-cadherin, ATF4, and CHOP proteins increased significantly (all P < 0.05). The changes in various indicators in the GSK2656157 group were the opposite of those in the GKB group (all P < 0.05). Compared with those in the GKB group, the cell activity, proliferation rate, migration rate, tumor volume, Ki-67 positive cell ratio, and expressions of MMP2, N-cadherin, and MMP9 proteins increased significantly in the GKB + GSK2656157 group (all P < 0.05), while the apoptosis rate, TUNEL positive cell ratio, and the expressions of p-PERK/PERK, E-cadherin, ATF4, and CHOP proteins reduced significantly (all P < 0.05). Conclusion: GKB can inhibit the proliferation, migration, and EMT of liver cancer MHCC-97H cells and promote their apoptosis by activating the PERK/ATF4/CHOP signaling pathway.
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