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

Abstract

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.

• Authors: Dat P Ha, Yuan-Li Tsai, Amy S Lee
• Journal: Neoplasia (New York, N.Y.) (Neoplasia) Vol. 23 Issue 12 Pg. 1213-1226 (12 2021) ISSN: 1476-5586 [Electronic] United States
• PMID: 34768108 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)
• Copyright: Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.

Chemical References

• Cardiac Glycosides
• Endoplasmic Reticulum Chaperone BiP
• HSPA5 protein, human
• Lanatosides
• lanatoside C

Topics

• Carcinoma, Pancreatic Ductal (metabolism)
• Cardiac Glycosides (pharmacology)
• Cell Line, Tumor
• Endoplasmic Reticulum Chaperone BiP (drug effects, metabolism)
• Endoplasmic Reticulum Stress (drug effects)
• Humans
• Lanatosides (pharmacology)
• Pancreatic Neoplasms (metabolism)
• Unfolded Protein Response (drug effects)
• Pancreatic Neoplasms