Inhibition of Sp1 prevents ER homeostasis and causes cell death by lysosomal membrane permeabilization in pancreatic cancer

Abstract Endoplasmic reticulum (ER) stress initiates an important mechanism for cell adaptation and survival, named the unfolded protein response (UPR). Severe or chronic/prolonged UPR can breach the threshold for survival and lead to cell death. There is a fundamental gap in knowledge on the molecu...

Descripción completa

Guardado en:

Detalles Bibliográficos
Autores principales:	Patricia Dauer, Vineet K. Gupta, Olivia McGinn, Alice Nomura, Nikita S. Sharma, Nivedita Arora, Bhuwan Giri, Vikas Dudeja, Ashok K. Saluja, Sulagna Banerjee
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2017
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/e14646c77c0341be9bc1d51784fe5589
Etiquetas:	Agregar Etiqueta Sin Etiquetas, Sea el primero en etiquetar este registro!

id	oai:doaj.org-article:e14646c77c0341be9bc1d51784fe5589
record_format	dspace
spelling	oai:doaj.org-article:e14646c77c0341be9bc1d51784fe55892021-12-02T15:05:28ZInhibition of Sp1 prevents ER homeostasis and causes cell death by lysosomal membrane permeabilization in pancreatic cancer10.1038/s41598-017-01696-22045-2322https://doaj.org/article/e14646c77c0341be9bc1d51784fe55892017-05-01T00:00:00Zhttps://doi.org/10.1038/s41598-017-01696-2https://doaj.org/toc/2045-2322Abstract Endoplasmic reticulum (ER) stress initiates an important mechanism for cell adaptation and survival, named the unfolded protein response (UPR). Severe or chronic/prolonged UPR can breach the threshold for survival and lead to cell death. There is a fundamental gap in knowledge on the molecular mechanism of how chronic ER stress is stimulated and leads to cell death in pancreatic ductal adenocarcinoma (PDAC). Our study shows that downregulating specificity protein 1 (Sp1), a transcription factor that is overexpressed in pancreatic cancer, activates UPR and results in chronic ER stress. In addition, downregulation of Sp1 results in its decreased binding to the ER stress response element present in the promoter region of Grp78, the master regulator of ER stress, thereby preventing homeostasis. We further show that inhibition of Sp1, as well as induction of ER stress, leads to lysosomal membrane permeabilization (LMP), a sustained accumulation of cytosolic calcium, and eventually cell death in pancreatic cancer.Patricia DauerVineet K. GuptaOlivia McGinnAlice NomuraNikita S. SharmaNivedita AroraBhuwan GiriVikas DudejaAshok K. SalujaSulagna BanerjeeNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 7, Iss 1, Pp 1-9 (2017)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Patricia Dauer Vineet K. Gupta Olivia McGinn Alice Nomura Nikita S. Sharma Nivedita Arora Bhuwan Giri Vikas Dudeja Ashok K. Saluja Sulagna Banerjee Inhibition of Sp1 prevents ER homeostasis and causes cell death by lysosomal membrane permeabilization in pancreatic cancer
description	Abstract Endoplasmic reticulum (ER) stress initiates an important mechanism for cell adaptation and survival, named the unfolded protein response (UPR). Severe or chronic/prolonged UPR can breach the threshold for survival and lead to cell death. There is a fundamental gap in knowledge on the molecular mechanism of how chronic ER stress is stimulated and leads to cell death in pancreatic ductal adenocarcinoma (PDAC). Our study shows that downregulating specificity protein 1 (Sp1), a transcription factor that is overexpressed in pancreatic cancer, activates UPR and results in chronic ER stress. In addition, downregulation of Sp1 results in its decreased binding to the ER stress response element present in the promoter region of Grp78, the master regulator of ER stress, thereby preventing homeostasis. We further show that inhibition of Sp1, as well as induction of ER stress, leads to lysosomal membrane permeabilization (LMP), a sustained accumulation of cytosolic calcium, and eventually cell death in pancreatic cancer.
format	article
author	Patricia Dauer Vineet K. Gupta Olivia McGinn Alice Nomura Nikita S. Sharma Nivedita Arora Bhuwan Giri Vikas Dudeja Ashok K. Saluja Sulagna Banerjee
author_facet	Patricia Dauer Vineet K. Gupta Olivia McGinn Alice Nomura Nikita S. Sharma Nivedita Arora Bhuwan Giri Vikas Dudeja Ashok K. Saluja Sulagna Banerjee
author_sort	Patricia Dauer
title	Inhibition of Sp1 prevents ER homeostasis and causes cell death by lysosomal membrane permeabilization in pancreatic cancer
title_short	Inhibition of Sp1 prevents ER homeostasis and causes cell death by lysosomal membrane permeabilization in pancreatic cancer
title_full	Inhibition of Sp1 prevents ER homeostasis and causes cell death by lysosomal membrane permeabilization in pancreatic cancer
title_fullStr	Inhibition of Sp1 prevents ER homeostasis and causes cell death by lysosomal membrane permeabilization in pancreatic cancer
title_full_unstemmed	Inhibition of Sp1 prevents ER homeostasis and causes cell death by lysosomal membrane permeabilization in pancreatic cancer
title_sort	inhibition of sp1 prevents er homeostasis and causes cell death by lysosomal membrane permeabilization in pancreatic cancer
publisher	Nature Portfolio
publishDate	2017
url	https://doaj.org/article/e14646c77c0341be9bc1d51784fe5589
work_keys_str_mv	AT patriciadauer inhibitionofsp1preventserhomeostasisandcausescelldeathbylysosomalmembranepermeabilizationinpancreaticcancer AT vineetkgupta inhibitionofsp1preventserhomeostasisandcausescelldeathbylysosomalmembranepermeabilizationinpancreaticcancer AT oliviamcginn inhibitionofsp1preventserhomeostasisandcausescelldeathbylysosomalmembranepermeabilizationinpancreaticcancer AT alicenomura inhibitionofsp1preventserhomeostasisandcausescelldeathbylysosomalmembranepermeabilizationinpancreaticcancer AT nikitassharma inhibitionofsp1preventserhomeostasisandcausescelldeathbylysosomalmembranepermeabilizationinpancreaticcancer AT niveditaarora inhibitionofsp1preventserhomeostasisandcausescelldeathbylysosomalmembranepermeabilizationinpancreaticcancer AT bhuwangiri inhibitionofsp1preventserhomeostasisandcausescelldeathbylysosomalmembranepermeabilizationinpancreaticcancer AT vikasdudeja inhibitionofsp1preventserhomeostasisandcausescelldeathbylysosomalmembranepermeabilizationinpancreaticcancer AT ashokksaluja inhibitionofsp1preventserhomeostasisandcausescelldeathbylysosomalmembranepermeabilizationinpancreaticcancer AT sulagnabanerjee inhibitionofsp1preventserhomeostasisandcausescelldeathbylysosomalmembranepermeabilizationinpancreaticcancer
_version_	1718388861837508608

Inhibition of Sp1 prevents ER homeostasis and causes cell death by lysosomal membrane permeabilization in pancreatic cancer

Ejemplares similares