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Kaposi’s sarcoma-associated herpesvirus viral protein kinase augments cell survival
Oncogenic viruses have developed various strategies to antagonize cell death and maintain lifelong persistence in their host, a relationship that may contribute to cancer development. Understanding how viruses inhibit cell death is essential for understanding viral oncogenesis. Kaposi’s sarcoma-asso...
Autores principales: | , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Nature Publishing Group UK
2023
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10585003/ https://www.ncbi.nlm.nih.gov/pubmed/37852997 http://dx.doi.org/10.1038/s41419-023-06193-1 |
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author | Wu, Xin-Jun Zhang, Zhigang Wong, Jason P. Rivera-Soto, Ricardo White, Maria C. Rai, Aryan A. Damania, Blossom |
author_facet | Wu, Xin-Jun Zhang, Zhigang Wong, Jason P. Rivera-Soto, Ricardo White, Maria C. Rai, Aryan A. Damania, Blossom |
author_sort | Wu, Xin-Jun |
collection | PubMed |
description | Oncogenic viruses have developed various strategies to antagonize cell death and maintain lifelong persistence in their host, a relationship that may contribute to cancer development. Understanding how viruses inhibit cell death is essential for understanding viral oncogenesis. Kaposi’s sarcoma-associated herpesvirus (KSHV) is associated with three different cancers in the human population, including Kaposi’s sarcoma (KS), the most common cancer in HIV patients. Previous studies have indicated that the KSHV-encoded viral protein kinase (vPK) impacts many processes dysregulated in tumorigenesis. Here, we report that vPK protects cells from apoptosis mediated by Caspase-3. Human umbilical vein endothelial cells (HUVECs) expressing vPK (HUVEC-vPK) have a survival advantage over control HUVEC under conditions of extrinsic- and intrinsic-mediated apoptosis. Abolishing the catalytic activity of vPK attenuated this survival advantage. We found that KSHV vPK-expressing HUVECs exhibited increased activation of cellular AKT kinase, a cell survival kinase, compared to control cells without vPK. In addition, we report that vPK directly binds the pleckstrin homology (PH) domain of AKT1 but not AKT2 or AKT3. Treatment of HUVEC-vPK cells with a pan-AKT inhibitor Miransertib (ARQ 092) reduced the overall phosphorylation of AKT, resulting in the cleavage of Caspase-3 and the induction of apoptosis. Furthermore, vPK expression activated VEGF/VEGFR2 in HUVECs and promoted angiogenesis through the AKT pathway. vPK expression also inhibited the cytotoxicity of cisplatin in vitro and in vivo. Collectively, our findings demonstrate that vPK’s ability to augment cell survival and promote angiogenesis is critically dependent on AKT signaling, which is relevant for future therapies for treating KSHV-associated cancers. |
format | Online Article Text |
id | pubmed-10585003 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2023 |
publisher | Nature Publishing Group UK |
record_format | MEDLINE/PubMed |
spelling | pubmed-105850032023-10-20 Kaposi’s sarcoma-associated herpesvirus viral protein kinase augments cell survival Wu, Xin-Jun Zhang, Zhigang Wong, Jason P. Rivera-Soto, Ricardo White, Maria C. Rai, Aryan A. Damania, Blossom Cell Death Dis Article Oncogenic viruses have developed various strategies to antagonize cell death and maintain lifelong persistence in their host, a relationship that may contribute to cancer development. Understanding how viruses inhibit cell death is essential for understanding viral oncogenesis. Kaposi’s sarcoma-associated herpesvirus (KSHV) is associated with three different cancers in the human population, including Kaposi’s sarcoma (KS), the most common cancer in HIV patients. Previous studies have indicated that the KSHV-encoded viral protein kinase (vPK) impacts many processes dysregulated in tumorigenesis. Here, we report that vPK protects cells from apoptosis mediated by Caspase-3. Human umbilical vein endothelial cells (HUVECs) expressing vPK (HUVEC-vPK) have a survival advantage over control HUVEC under conditions of extrinsic- and intrinsic-mediated apoptosis. Abolishing the catalytic activity of vPK attenuated this survival advantage. We found that KSHV vPK-expressing HUVECs exhibited increased activation of cellular AKT kinase, a cell survival kinase, compared to control cells without vPK. In addition, we report that vPK directly binds the pleckstrin homology (PH) domain of AKT1 but not AKT2 or AKT3. Treatment of HUVEC-vPK cells with a pan-AKT inhibitor Miransertib (ARQ 092) reduced the overall phosphorylation of AKT, resulting in the cleavage of Caspase-3 and the induction of apoptosis. Furthermore, vPK expression activated VEGF/VEGFR2 in HUVECs and promoted angiogenesis through the AKT pathway. vPK expression also inhibited the cytotoxicity of cisplatin in vitro and in vivo. Collectively, our findings demonstrate that vPK’s ability to augment cell survival and promote angiogenesis is critically dependent on AKT signaling, which is relevant for future therapies for treating KSHV-associated cancers. Nature Publishing Group UK 2023-10-18 /pmc/articles/PMC10585003/ /pubmed/37852997 http://dx.doi.org/10.1038/s41419-023-06193-1 Text en © The Author(s) 2023 https://creativecommons.org/licenses/by/4.0/Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) . |
spellingShingle | Article Wu, Xin-Jun Zhang, Zhigang Wong, Jason P. Rivera-Soto, Ricardo White, Maria C. Rai, Aryan A. Damania, Blossom Kaposi’s sarcoma-associated herpesvirus viral protein kinase augments cell survival |
title | Kaposi’s sarcoma-associated herpesvirus viral protein kinase augments cell survival |
title_full | Kaposi’s sarcoma-associated herpesvirus viral protein kinase augments cell survival |
title_fullStr | Kaposi’s sarcoma-associated herpesvirus viral protein kinase augments cell survival |
title_full_unstemmed | Kaposi’s sarcoma-associated herpesvirus viral protein kinase augments cell survival |
title_short | Kaposi’s sarcoma-associated herpesvirus viral protein kinase augments cell survival |
title_sort | kaposi’s sarcoma-associated herpesvirus viral protein kinase augments cell survival |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10585003/ https://www.ncbi.nlm.nih.gov/pubmed/37852997 http://dx.doi.org/10.1038/s41419-023-06193-1 |
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