PTEN inhibitor bpV(HOpic) confers protection against ionizing radiation

Abstract Exposure to Ionizing radiation (IR) poses a severe threat to human health. Therefore, there is an urgent need to develop potent and safe radioprotective agents for radio-nuclear emergencies. Phosphatidylinositol-3-kinase (PI3K) mediates its cytoprotective signaling against IR by phosphoryla...

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Autores principales:	Ankit Chauhan, Dhananjay Kumar Sah, Neeraj Kumari, Namita Kalra, Ravi Soni, Anant Narayan Bhatt
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2021
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/dd66afc93afb4075b4f20825db39680b
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spelling	oai:doaj.org-article:dd66afc93afb4075b4f20825db39680b2021-12-02T13:48:41ZPTEN inhibitor bpV(HOpic) confers protection against ionizing radiation10.1038/s41598-020-80754-82045-2322https://doaj.org/article/dd66afc93afb4075b4f20825db39680b2021-01-01T00:00:00Zhttps://doi.org/10.1038/s41598-020-80754-8https://doaj.org/toc/2045-2322Abstract Exposure to Ionizing radiation (IR) poses a severe threat to human health. Therefore, there is an urgent need to develop potent and safe radioprotective agents for radio-nuclear emergencies. Phosphatidylinositol-3-kinase (PI3K) mediates its cytoprotective signaling against IR by phosphorylating membrane phospholipids to phosphatidylinositol 3,4,5 triphosphate, PIP3, that serve as a docking site for AKT. Phosphatase and Tensin Homolog on chromosome 10 (PTEN) antagonizes PI3K activity by dephosphorylating PIP3, thus suppressing PI3K/AKT signaling that could prevent IR induced cytotoxicity. The current study was undertaken to investigate the radioprotective potential of PTEN inhibitor (PTENi), bpV(HOpic). The cell cytotoxicity, proliferation index, and clonogenic survival assays were performed for assessing the radioprotective potential of bpV(HOpic). A safe dose of bpV(HOpic) was shown to be radioprotective in three radiosensitive tissue origin cells. Further, bpV(HOpic) significantly reduced the IR-induced apoptosis and associated pro-death signaling. A faster and better DNA repair kinetics was also observed in bpV(HOpic) pretreated cells exposed to IR. Additionally, bpV(HOpic) decreased the IR-induced oxidative stress and significantly enhanced the antioxidant defense mechanism in cells. The radioprotective effect of bpV(HOpic) was found to be AKT dependant and primarily regulated by the enhanced glycolysis and associated signaling. Furthermore, this in-vitro observation was verified in-vivo, where administration of bpV(HOpic) in C57BL/6 mice resulted in AKT activation and conferred survival advantage against IR-induced mortality. These results imply that bpV(HOpic) ameliorates IR-induced oxidative stress and cell death by inducing AKT signaling mediated antioxidant defense system and DNA repair pathways, thus strengthening its potential to be used as a radiation countermeasure.Ankit ChauhanDhananjay Kumar SahNeeraj KumariNamita KalraRavi SoniAnant Narayan BhattNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 11, Iss 1, Pp 1-17 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Ankit Chauhan Dhananjay Kumar Sah Neeraj Kumari Namita Kalra Ravi Soni Anant Narayan Bhatt PTEN inhibitor bpV(HOpic) confers protection against ionizing radiation
description	Abstract Exposure to Ionizing radiation (IR) poses a severe threat to human health. Therefore, there is an urgent need to develop potent and safe radioprotective agents for radio-nuclear emergencies. Phosphatidylinositol-3-kinase (PI3K) mediates its cytoprotective signaling against IR by phosphorylating membrane phospholipids to phosphatidylinositol 3,4,5 triphosphate, PIP3, that serve as a docking site for AKT. Phosphatase and Tensin Homolog on chromosome 10 (PTEN) antagonizes PI3K activity by dephosphorylating PIP3, thus suppressing PI3K/AKT signaling that could prevent IR induced cytotoxicity. The current study was undertaken to investigate the radioprotective potential of PTEN inhibitor (PTENi), bpV(HOpic). The cell cytotoxicity, proliferation index, and clonogenic survival assays were performed for assessing the radioprotective potential of bpV(HOpic). A safe dose of bpV(HOpic) was shown to be radioprotective in three radiosensitive tissue origin cells. Further, bpV(HOpic) significantly reduced the IR-induced apoptosis and associated pro-death signaling. A faster and better DNA repair kinetics was also observed in bpV(HOpic) pretreated cells exposed to IR. Additionally, bpV(HOpic) decreased the IR-induced oxidative stress and significantly enhanced the antioxidant defense mechanism in cells. The radioprotective effect of bpV(HOpic) was found to be AKT dependant and primarily regulated by the enhanced glycolysis and associated signaling. Furthermore, this in-vitro observation was verified in-vivo, where administration of bpV(HOpic) in C57BL/6 mice resulted in AKT activation and conferred survival advantage against IR-induced mortality. These results imply that bpV(HOpic) ameliorates IR-induced oxidative stress and cell death by inducing AKT signaling mediated antioxidant defense system and DNA repair pathways, thus strengthening its potential to be used as a radiation countermeasure.
format	article
author	Ankit Chauhan Dhananjay Kumar Sah Neeraj Kumari Namita Kalra Ravi Soni Anant Narayan Bhatt
author_facet	Ankit Chauhan Dhananjay Kumar Sah Neeraj Kumari Namita Kalra Ravi Soni Anant Narayan Bhatt
author_sort	Ankit Chauhan
title	PTEN inhibitor bpV(HOpic) confers protection against ionizing radiation
title_short	PTEN inhibitor bpV(HOpic) confers protection against ionizing radiation
title_full	PTEN inhibitor bpV(HOpic) confers protection against ionizing radiation
title_fullStr	PTEN inhibitor bpV(HOpic) confers protection against ionizing radiation
title_full_unstemmed	PTEN inhibitor bpV(HOpic) confers protection against ionizing radiation
title_sort	pten inhibitor bpv(hopic) confers protection against ionizing radiation
publisher	Nature Portfolio
publishDate	2021
url	https://doaj.org/article/dd66afc93afb4075b4f20825db39680b
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PTEN inhibitor bpV(HOpic) confers protection against ionizing radiation

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