Suppression of ER-stress induction of GRP78 as an anti-neoplastic mechanism of the cardiac glycoside Lanatoside C in pancreatic cancer

The 78 kilodalton glucose-regulated protein (GRP78) is a major endoplasmic reticulum (ER) molecular chaperone with antiapoptotic properties and a key regulator of the unfolded protein response (UPR). ER-stress induction of GRP78 in cancer cells represents a major pro-survival branch of the UPR. Panc...

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Autores principales:	Dat P. Ha, Yuan-Li Tsai, Amy S. Lee
Formato:	article
Lenguaje:	EN
Publicado:	Elsevier 2021
Materias:	GRP78 BiP ER-stress Cardiac Glycosides Lanatoside C Pancreatic Cancer Neoplasms. Tumors. Oncology. Including cancer and carcinogens RC254-282
Acceso en línea:	https://doaj.org/article/0df6786ddc6d40c6932382b12c33996e
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spelling	oai:doaj.org-article:0df6786ddc6d40c6932382b12c33996e2021-11-30T04:14:37ZSuppression of ER-stress induction of GRP78 as an anti-neoplastic mechanism of the cardiac glycoside Lanatoside C in pancreatic cancer1476-558610.1016/j.neo.2021.10.004https://doaj.org/article/0df6786ddc6d40c6932382b12c33996e2021-12-01T00:00:00Zhttp://www.sciencedirect.com/science/article/pii/S1476558621000890https://doaj.org/toc/1476-5586The 78 kilodalton glucose-regulated protein (GRP78) is a major endoplasmic reticulum (ER) molecular chaperone with antiapoptotic properties and a key regulator of the unfolded protein response (UPR). ER-stress induction of GRP78 in cancer cells represents a major pro-survival branch of the UPR. Pancreatic ductal adenocarcinoma (PDAC) remains a highly lethal disease and high level of GRP78 is associated with aggressive disease and poor survival. Recently, we reported that PDAC exhibited high level of ER stress and that GRP78 haploinsufficiency is sufficient to suppress pancreatic tumorigenesis in mice, suggesting the utility of inhibitors of GRP78 expression in combating pancreatic cancer. Screening of clinically relevant compound libraries revealed that cardiac glycosides (CGs) can inhibit ER-stress induction of GRP78 in pancreatic and other types of human cancers. Using the FDA-approved CG compound Lanatoside C (LanC) and human pancreatic cancer cell lines as model systems, we discovered that LanC preferably suppressed ER stress induction of GRP78 and to a lesser extent GRP94. The suppression is at the post-transcriptional level and dependent on the Na+/K+-ATPase ion pump. Overexpression of GRP78 mitigates apoptotic activities of LanC in ER stressed cells. Our study revealed a new function of CGs as inhibitor of stress induction of GRP78, and that this suppression at least in part contributes to the apoptotic activities of CGs in human pancreatic cancer cells in vitro. These findings support further investigation into CGs as potential antineoplastic agents for pancreatic and other cancers which depend on GRP78 for growth and survival.Dat P. HaYuan-Li TsaiAmy S. LeeElsevierarticleGRP78BiPER-stressCardiac GlycosidesLanatoside CPancreatic CancerNeoplasms. Tumors. Oncology. Including cancer and carcinogensRC254-282ENNeoplasia: An International Journal for Oncology Research, Vol 23, Iss 12, Pp 1213-1226 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	GRP78 BiP ER-stress Cardiac Glycosides Lanatoside C Pancreatic Cancer Neoplasms. Tumors. Oncology. Including cancer and carcinogens RC254-282
spellingShingle	GRP78 BiP ER-stress Cardiac Glycosides Lanatoside C Pancreatic Cancer Neoplasms. Tumors. Oncology. Including cancer and carcinogens RC254-282 Dat P. Ha Yuan-Li Tsai Amy S. Lee Suppression of ER-stress induction of GRP78 as an anti-neoplastic mechanism of the cardiac glycoside Lanatoside C in pancreatic cancer
description	The 78 kilodalton glucose-regulated protein (GRP78) is a major endoplasmic reticulum (ER) molecular chaperone with antiapoptotic properties and a key regulator of the unfolded protein response (UPR). ER-stress induction of GRP78 in cancer cells represents a major pro-survival branch of the UPR. Pancreatic ductal adenocarcinoma (PDAC) remains a highly lethal disease and high level of GRP78 is associated with aggressive disease and poor survival. Recently, we reported that PDAC exhibited high level of ER stress and that GRP78 haploinsufficiency is sufficient to suppress pancreatic tumorigenesis in mice, suggesting the utility of inhibitors of GRP78 expression in combating pancreatic cancer. Screening of clinically relevant compound libraries revealed that cardiac glycosides (CGs) can inhibit ER-stress induction of GRP78 in pancreatic and other types of human cancers. Using the FDA-approved CG compound Lanatoside C (LanC) and human pancreatic cancer cell lines as model systems, we discovered that LanC preferably suppressed ER stress induction of GRP78 and to a lesser extent GRP94. The suppression is at the post-transcriptional level and dependent on the Na+/K+-ATPase ion pump. Overexpression of GRP78 mitigates apoptotic activities of LanC in ER stressed cells. Our study revealed a new function of CGs as inhibitor of stress induction of GRP78, and that this suppression at least in part contributes to the apoptotic activities of CGs in human pancreatic cancer cells in vitro. These findings support further investigation into CGs as potential antineoplastic agents for pancreatic and other cancers which depend on GRP78 for growth and survival.
format	article
author	Dat P. Ha Yuan-Li Tsai Amy S. Lee
author_facet	Dat P. Ha Yuan-Li Tsai Amy S. Lee
author_sort	Dat P. Ha
title	Suppression of ER-stress induction of GRP78 as an anti-neoplastic mechanism of the cardiac glycoside Lanatoside C in pancreatic cancer
title_short	Suppression of ER-stress induction of GRP78 as an anti-neoplastic mechanism of the cardiac glycoside Lanatoside C in pancreatic cancer
title_full	Suppression of ER-stress induction of GRP78 as an anti-neoplastic mechanism of the cardiac glycoside Lanatoside C in pancreatic cancer
title_fullStr	Suppression of ER-stress induction of GRP78 as an anti-neoplastic mechanism of the cardiac glycoside Lanatoside C in pancreatic cancer
title_full_unstemmed	Suppression of ER-stress induction of GRP78 as an anti-neoplastic mechanism of the cardiac glycoside Lanatoside C in pancreatic cancer
title_sort	suppression of er-stress induction of grp78 as an anti-neoplastic mechanism of the cardiac glycoside lanatoside c in pancreatic cancer
publisher	Elsevier
publishDate	2021
url	https://doaj.org/article/0df6786ddc6d40c6932382b12c33996e
work_keys_str_mv	AT datpha suppressionoferstressinductionofgrp78asanantineoplasticmechanismofthecardiacglycosidelanatosidecinpancreaticcancer AT yuanlitsai suppressionoferstressinductionofgrp78asanantineoplasticmechanismofthecardiacglycosidelanatosidecinpancreaticcancer AT amyslee suppressionoferstressinductionofgrp78asanantineoplasticmechanismofthecardiacglycosidelanatosidecinpancreaticcancer
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Suppression of ER-stress induction of GRP78 as an anti-neoplastic mechanism of the cardiac glycoside Lanatoside C in pancreatic cancer

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