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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...

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Autores principales: Wu, Xin-Jun, Zhang, Zhigang, Wong, Jason P., Rivera-Soto, Ricardo, White, Maria C., Rai, Aryan A., Damania, Blossom
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group UK 2023
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.
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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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