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

Patricia Dauer, Vineet K. Gupta, Olivia McGinn, Alice Nomura, Nikita S. Sharma, Nivedita Arora, Bhuwan Giri, Vikas Dudeja, Ashok Saluja, Sulagna Banerjee

Research output: Contribution to journalArticle

3 Citations (Scopus)

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.

Original languageEnglish (US)
Article number1564
JournalScientific Reports
Volume7
Issue number1
DOIs
StatePublished - Dec 1 2017

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Endoplasmic Reticulum Stress
Pancreatic Neoplasms
Endoplasmic Reticulum
Cause of Death
Homeostasis
Cell Death
Unfolded Protein Response
Membranes
Proteins
Down-Regulation
Sp1 Transcription Factor
Response Elements
Genetic Promoter Regions
Cell Survival
Adenocarcinoma
Calcium

ASJC Scopus subject areas

  • General

Cite this

Inhibition of Sp1 prevents ER homeostasis and causes cell death by lysosomal membrane permeabilization in pancreatic cancer. / Dauer, Patricia; Gupta, Vineet K.; McGinn, Olivia; Nomura, Alice; Sharma, Nikita S.; Arora, Nivedita; Giri, Bhuwan; Dudeja, Vikas; Saluja, Ashok; Banerjee, Sulagna.

In: Scientific Reports, Vol. 7, No. 1, 1564, 01.12.2017.

Research output: Contribution to journalArticle

Dauer, Patricia ; Gupta, Vineet K. ; McGinn, Olivia ; Nomura, Alice ; Sharma, Nikita S. ; Arora, Nivedita ; Giri, Bhuwan ; Dudeja, Vikas ; Saluja, Ashok ; Banerjee, Sulagna. / Inhibition of Sp1 prevents ER homeostasis and causes cell death by lysosomal membrane permeabilization in pancreatic cancer. In: Scientific Reports. 2017 ; Vol. 7, No. 1.
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AU - Sharma, Nikita S.

AU - Arora, Nivedita

AU - Giri, Bhuwan

AU - Dudeja, Vikas

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