Interplay of aurora kinase a functional residues and Epstein-barr Nuclear Antigen 1 in Epstein-barr virus associated Gastric cancer using AGS cells
Abstract Epstein-Barr virus (EBV), an oncogenic gamma-herpesvirus, belongs to group 1 carcinogen and is implicated in various cancers, including gastric cancer. Aurora Kinase A is a major mitotic protein kinase that regulates mitotic progression; overexpression and hyperactivation of AURKA commonly...
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2025-01-01
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| author | Nidhi Varshney Siddharth Singh Meenakshi Kandpal Vaishali Saini Erle S. Roberston Hem Chandra Jha |
| author_facet | Nidhi Varshney Siddharth Singh Meenakshi Kandpal Vaishali Saini Erle S. Roberston Hem Chandra Jha |
| author_sort | Nidhi Varshney |
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| description | Abstract Epstein-Barr virus (EBV), an oncogenic gamma-herpesvirus, belongs to group 1 carcinogen and is implicated in various cancers, including gastric cancer. Aurora Kinase A is a major mitotic protein kinase that regulates mitotic progression; overexpression and hyperactivation of AURKA commonly promote genomic instability in many tumours. However, the relationship of functional residues of AURKA and EBV in gastric cancer progression remains unknown. We reveal that AURKA overexpression and EBV infection induce aneuploidy in gastric epithelial cells. The AURKA (S89) N-terminal residue is critical for the centrosome maturation process in EBV-infected gastric epithelial cells. The kinase domain residues T287 and T288 of AURKA are essential for centrosome maturation and bipolar spindle formation in EBV-infected gastric cancer cells. We also show that AURKA 287/288 dm reduces the transcript expression of cell cycle markers involved in mitotic entry in EBV infection. This mutant also enhanced the protein expression of p53 and Rb, which was reduced in EBV infection and decreased the Survivin expression. Further, EBNA1, the latent gene of EBV, stabilises the AURKA in its wild-type form and S89A mutant but unable to stabilise in T287/288A double mutant. These mutants also induce mitotic catastrophe by regulating the apoptosis and autophagy pathway in EBV infection. AURKA287/288 dm also promotes autophagosome formation even in EBV infection. Thus, this study demonstrates that the AURKA kinase domain is essential for its functioning and progression of the oncogenesis of EBV-infected gastric epithelial cells. |
| format | Article |
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| institution | Kabale University |
| issn | 1471-2407 |
| language | English |
| publishDate | 2025-01-01 |
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| series | BMC Cancer |
| spelling | doaj-art-a6a4fb59b3924bb284721f95cbb9f8522025-01-26T12:37:57ZengBMCBMC Cancer1471-24072025-01-0125111610.1186/s12885-024-13260-zInterplay of aurora kinase a functional residues and Epstein-barr Nuclear Antigen 1 in Epstein-barr virus associated Gastric cancer using AGS cellsNidhi Varshney0Siddharth Singh1Meenakshi Kandpal2Vaishali Saini3Erle S. Roberston4Hem Chandra Jha5Department of Biosciences and Biomedical Engineering, Indian Institute of Technology IndoreDepartment of Biosciences and Biomedical Engineering, Indian Institute of Technology IndoreDepartment of Biosciences and Biomedical Engineering, Indian Institute of Technology IndoreDepartment of Biosciences and Biomedical Engineering, Indian Institute of Technology IndoreDepartment of Microbiology and the Tumor Virology Program, Abramson Cancer Center, Perelman School of Medicine at the University of PennsylvaniaDepartment of Biosciences and Biomedical Engineering, Indian Institute of Technology IndoreAbstract Epstein-Barr virus (EBV), an oncogenic gamma-herpesvirus, belongs to group 1 carcinogen and is implicated in various cancers, including gastric cancer. Aurora Kinase A is a major mitotic protein kinase that regulates mitotic progression; overexpression and hyperactivation of AURKA commonly promote genomic instability in many tumours. However, the relationship of functional residues of AURKA and EBV in gastric cancer progression remains unknown. We reveal that AURKA overexpression and EBV infection induce aneuploidy in gastric epithelial cells. The AURKA (S89) N-terminal residue is critical for the centrosome maturation process in EBV-infected gastric epithelial cells. The kinase domain residues T287 and T288 of AURKA are essential for centrosome maturation and bipolar spindle formation in EBV-infected gastric cancer cells. We also show that AURKA 287/288 dm reduces the transcript expression of cell cycle markers involved in mitotic entry in EBV infection. This mutant also enhanced the protein expression of p53 and Rb, which was reduced in EBV infection and decreased the Survivin expression. Further, EBNA1, the latent gene of EBV, stabilises the AURKA in its wild-type form and S89A mutant but unable to stabilise in T287/288A double mutant. These mutants also induce mitotic catastrophe by regulating the apoptosis and autophagy pathway in EBV infection. AURKA287/288 dm also promotes autophagosome formation even in EBV infection. Thus, this study demonstrates that the AURKA kinase domain is essential for its functioning and progression of the oncogenesis of EBV-infected gastric epithelial cells.https://doi.org/10.1186/s12885-024-13260-zAurora Kinase AGastric cancerEpstein-Barr VirusEpstein-Barr Nuclear Antigen 1Microtubule polymerisationStability assay |
| spellingShingle | Nidhi Varshney Siddharth Singh Meenakshi Kandpal Vaishali Saini Erle S. Roberston Hem Chandra Jha Interplay of aurora kinase a functional residues and Epstein-barr Nuclear Antigen 1 in Epstein-barr virus associated Gastric cancer using AGS cells BMC Cancer Aurora Kinase A Gastric cancer Epstein-Barr Virus Epstein-Barr Nuclear Antigen 1 Microtubule polymerisation Stability assay |
| title | Interplay of aurora kinase a functional residues and Epstein-barr Nuclear Antigen 1 in Epstein-barr virus associated Gastric cancer using AGS cells |
| title_full | Interplay of aurora kinase a functional residues and Epstein-barr Nuclear Antigen 1 in Epstein-barr virus associated Gastric cancer using AGS cells |
| title_fullStr | Interplay of aurora kinase a functional residues and Epstein-barr Nuclear Antigen 1 in Epstein-barr virus associated Gastric cancer using AGS cells |
| title_full_unstemmed | Interplay of aurora kinase a functional residues and Epstein-barr Nuclear Antigen 1 in Epstein-barr virus associated Gastric cancer using AGS cells |
| title_short | Interplay of aurora kinase a functional residues and Epstein-barr Nuclear Antigen 1 in Epstein-barr virus associated Gastric cancer using AGS cells |
| title_sort | interplay of aurora kinase a functional residues and epstein barr nuclear antigen 1 in epstein barr virus associated gastric cancer using ags cells |
| topic | Aurora Kinase A Gastric cancer Epstein-Barr Virus Epstein-Barr Nuclear Antigen 1 Microtubule polymerisation Stability assay |
| url | https://doi.org/10.1186/s12885-024-13260-z |
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