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Upregulation of Glucose-Regulated Protein 78 in Metastatic Cancer Cells Is Necessary for Lung Metastasis Progression.

Authors :
Lizardo MM
Morrow JJ
Miller TE
Hong ES
Ren L
Mendoza A
Halsey CH
Scacheri PC
Helman LJ
Khanna C
Source :
Neoplasia (New York, N.Y.) [Neoplasia] 2016 Nov; Vol. 18 (11), pp. 699-710. Date of Electronic Publication: 2016 Oct 28.
Publication Year :
2016

Abstract

Metastasis is the cause of more than 90% of all cancer deaths. Despite this fact, most anticancer therapeutics currently in clinical use have limited efficacy in treating established metastases. Here, we identify the endoplasmic reticulum chaperone protein, glucose-regulated protein 78 (GRP78), as a metastatic dependency in several highly metastatic cancer cell models. We find that GRP78 is consistently upregulated when highly metastatic cancer cells colonize the lung microenvironment and that mitigation of GRP78 upregulation via short hairpin RNA or treatment with the small molecule IT-139, which is currently under clinical investigation for the treatment of primary tumors, inhibits metastatic growth in the lung microenvironment. Inhibition of GRP78 upregulation and an associated reduction in metastatic potential have been shown in four highly metastatic cell line models: three human osteosarcomas and one murine mammary adenocarcinoma. Lastly, we show that downmodulation of GRP78 in highly metastatic cancer cells significantly increases median survival times in our in vivo animal model of experimental metastasis. Collectively, our data indicate that GRP78 is an attractive target for the development of antimetastatic therapies.<br /> (Published by Elsevier Inc.)

Details

Language :
English
ISSN :
1476-5586
Volume :
18
Issue :
11
Database :
MEDLINE
Journal :
Neoplasia (New York, N.Y.)
Publication Type :
Academic Journal
Accession number :
27973325
Full Text :
https://doi.org/10.1016/j.neo.2016.09.001