title: Upregulation of Glucose-Regulated Protein 78 in Metastatic Cancer Cells Is Necessary for Lung Metastasis Progression.
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.
authors.affiliation: Pediatric Oncology Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA.
authors.forename: Michael M
authors.initials: MM
authors.lastname: Lizardo
authors.affiliation: Department of Genetics and Genome Sciences, School of Medicine, Case Western Reserve University, Cleveland, OH, USA; Department of Pathology, Case Western Reserve University, Cleveland, OH, USA.
authors.forename: James J
authors.initials: JJ
authors.lastname: Morrow
authors.affiliation: Department of Genetics and Genome Sciences, School of Medicine, Case Western Reserve University, Cleveland, OH, USA; Department of Pathology, Case Western Reserve University, Cleveland, OH, USA.
authors.forename: Tyler E
authors.initials: TE
authors.lastname: Miller
authors.affiliation: Pediatric Oncology Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA.
authors.forename: Ellen S
authors.initials: ES
authors.lastname: Hong
authors.affiliation: Comparative Oncology Program, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA.
authors.forename: Ling
authors.initials: L
authors.lastname: Ren
authors.affiliation: Pediatric Oncology Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA.
authors.forename: Arnulfo
authors.initials: A
authors.lastname: Mendoza
authors.affiliation: Laboratory of Cancer Biology and Genetics, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA.
authors.forename: Charles H
authors.initials: CH
authors.lastname: Halsey
authors.affiliation: Department of Genetics and Genome Sciences, School of Medicine, Case Western Reserve University, Cleveland, OH, USA.
authors.forename: Peter C
authors.initials: PC
authors.lastname: Scacheri
authors.affiliation: Pediatric Oncology Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA.
authors.forename: Lee J
authors.initials: LJ
authors.lastname: Helman
authors.affiliation: Pediatric Oncology Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA; Ethos Discovery in Washington DC and Ethos Veterinary Health, Wolburn MA, USA. Electronic address: ckhanna@animalci.com.
authors.forename: Chand
authors.initials: C
authors.lastname: Khanna