GRP78/BiP determines senescence evasion cell fate after cisplatin-based chemotherapy

Abstract Cisplatin (CDDP) induces senescence characterized by senescence-associated secretory phenotypes (SASP) and the unfolded protein response (UPR). In this study, we investigated the proteins related to the UPR during the senescence cell fate. Strikingly, we found that one of the critical ER-re...

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Autores principales:	Zin Zin Ei, Kanuengnit Choochuay, Alisa Tubsuwan, Decha Pinkaew, Maneewan Suksomtip, Chanida Vinayanuwattikun, Pithi Chanvorachote, Preedakorn Chunhacha
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2021
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/ad6d1a96e493418c8a33cafca4d13c0c
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spelling	oai:doaj.org-article:ad6d1a96e493418c8a33cafca4d13c0c2021-11-21T12:16:45ZGRP78/BiP determines senescence evasion cell fate after cisplatin-based chemotherapy10.1038/s41598-021-01540-82045-2322https://doaj.org/article/ad6d1a96e493418c8a33cafca4d13c0c2021-11-01T00:00:00Zhttps://doi.org/10.1038/s41598-021-01540-8https://doaj.org/toc/2045-2322Abstract Cisplatin (CDDP) induces senescence characterized by senescence-associated secretory phenotypes (SASP) and the unfolded protein response (UPR). In this study, we investigated the proteins related to the UPR during the senescence cell fate. Strikingly, we found that one of the critical ER-resident proteins, GRP78/BiP, was significantly altered. Here we show that GRP78 levels differentially expressed depending on non-small lung cancer subtypes. GRP78 indeed regulates the evasion of senescence in adenocarcinoma A549 cells, in which the increased GRP78 levels enable them to re-proliferate after CDDP removal. Conversely, GRP78 is downregulated in the senescence H460 cells, making them lacking senescence evasion capability. We observed that the translational regulation critically contributed to the GRP78 protein levels in CDDP-induces senescence. Furthermore, the increased GRP78 level during senescence confers resistance to senolytic drug, Bortezomib, as observed by a twofold increase in IC50 in A549 senescence cells compared to the wild-type. This observation is also consistent in the cells that have undergone genetic manipulation by transfection with pcDNA3.1(+)-GRP78/BiP plasmids and pSpCas9(BB)-2A-Puro containing guide RNA sequence targeting GRP78 exon 3 to induce the overexpression and downregulation of GRP78 in H460 cells, respectively. Our findings reveal a unique role of GRP78 on the senescence evasion cell fate and senolytic drug resistance after cisplatin-based chemotherapy.Zin Zin EiKanuengnit ChoochuayAlisa TubsuwanDecha PinkaewManeewan SuksomtipChanida VinayanuwattikunPithi ChanvorachotePreedakorn ChunhachaNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 11, Iss 1, Pp 1-15 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Zin Zin Ei Kanuengnit Choochuay Alisa Tubsuwan Decha Pinkaew Maneewan Suksomtip Chanida Vinayanuwattikun Pithi Chanvorachote Preedakorn Chunhacha GRP78/BiP determines senescence evasion cell fate after cisplatin-based chemotherapy
description	Abstract Cisplatin (CDDP) induces senescence characterized by senescence-associated secretory phenotypes (SASP) and the unfolded protein response (UPR). In this study, we investigated the proteins related to the UPR during the senescence cell fate. Strikingly, we found that one of the critical ER-resident proteins, GRP78/BiP, was significantly altered. Here we show that GRP78 levels differentially expressed depending on non-small lung cancer subtypes. GRP78 indeed regulates the evasion of senescence in adenocarcinoma A549 cells, in which the increased GRP78 levels enable them to re-proliferate after CDDP removal. Conversely, GRP78 is downregulated in the senescence H460 cells, making them lacking senescence evasion capability. We observed that the translational regulation critically contributed to the GRP78 protein levels in CDDP-induces senescence. Furthermore, the increased GRP78 level during senescence confers resistance to senolytic drug, Bortezomib, as observed by a twofold increase in IC50 in A549 senescence cells compared to the wild-type. This observation is also consistent in the cells that have undergone genetic manipulation by transfection with pcDNA3.1(+)-GRP78/BiP plasmids and pSpCas9(BB)-2A-Puro containing guide RNA sequence targeting GRP78 exon 3 to induce the overexpression and downregulation of GRP78 in H460 cells, respectively. Our findings reveal a unique role of GRP78 on the senescence evasion cell fate and senolytic drug resistance after cisplatin-based chemotherapy.
format	article
author	Zin Zin Ei Kanuengnit Choochuay Alisa Tubsuwan Decha Pinkaew Maneewan Suksomtip Chanida Vinayanuwattikun Pithi Chanvorachote Preedakorn Chunhacha
author_facet	Zin Zin Ei Kanuengnit Choochuay Alisa Tubsuwan Decha Pinkaew Maneewan Suksomtip Chanida Vinayanuwattikun Pithi Chanvorachote Preedakorn Chunhacha
author_sort	Zin Zin Ei
title	GRP78/BiP determines senescence evasion cell fate after cisplatin-based chemotherapy
title_short	GRP78/BiP determines senescence evasion cell fate after cisplatin-based chemotherapy
title_full	GRP78/BiP determines senescence evasion cell fate after cisplatin-based chemotherapy
title_fullStr	GRP78/BiP determines senescence evasion cell fate after cisplatin-based chemotherapy
title_full_unstemmed	GRP78/BiP determines senescence evasion cell fate after cisplatin-based chemotherapy
title_sort	grp78/bip determines senescence evasion cell fate after cisplatin-based chemotherapy
publisher	Nature Portfolio
publishDate	2021
url	https://doaj.org/article/ad6d1a96e493418c8a33cafca4d13c0c
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GRP78/BiP determines senescence evasion cell fate after cisplatin-based chemotherapy

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