title: Cell surface GRP78 facilitates hepatoma cells proliferation and migration by activating IGF-IR.
abstract: The 78kDa glucose regulated protein (GRP78) is a multifunctional chaperone that is involved in a variety of cellular processes. Insulin like growth factor I receptor (IGF-IR) often aberrant expresses in many types of tumor cells. The IGF-IR signaling plays key roles in carcinogenesis and maintenance of the malignant phenotype. The crosstalk between GRP78 and IGF-IR molecules has not well been illuminated. Here, we demonstrated a reciprocal regulation of GRP78 expression and IGF-IR pathway activation. IGF-I induced GRP78 expression in hepatoma cells. IGF-IR knockdown or IGF-IR inhibitor repressed GRP78 expression. Both phosphatidylinositol 3-kianase (PI3K) and mitogen-activated protein kinase (MAPK) pathways involved in IGF-I induction of GRP78 expression. Interestingly, treatment of hepatoma cells with IGF-I re-distributes GRP78 from endoplasmic reticulum (ER) to cell surface and promotes its physical interaction with IGF-IR. Also, GRP78 promotes IGF-IR phosphorylation and activation. Blocked of GRP78 by small interfering RNA or inhibition of GRP78 function by (-)-epigallocatechin gallate (EGCG) blocks IGF-I induced IGF-IR phosphorylation and its downstream signaling. Further, blocked cell surface GRP78 with antibody inhibits IGF-I stimulated cellular proliferation and migration. These data reveal an essential role for the molecular chaperone GRP78 in IGF-IR signaling and implicate the use of GRP78 inhibitors in blocking IGF-IR signaling in hepatoma cells.
authors.affiliation: Taishan Scholar Immunology Program, Binzhou Medical University, Yantai, Shandong 264003, China; Medicine and Pharmacy Research Center, Binzhou Medical University, Yantai 264003, Shandong Province, China.
authors.forename: Yancun
authors.initials: Y
authors.lastname: Yin
authors.affiliation: Taishan Scholar Immunology Program, Binzhou Medical University, Yantai, Shandong 264003, China.
authors.forename: Chen
authors.initials: C
authors.lastname: Chen
authors.affiliation: Taishan Scholar Immunology Program, Binzhou Medical University, Yantai, Shandong 264003, China.
authors.forename: Jinliang
authors.initials: J
authors.lastname: Chen
authors.affiliation: Taishan Scholar Immunology Program, Binzhou Medical University, Yantai, Shandong 264003, China.
authors.forename: Renhui
authors.initials: R
authors.lastname: Zhan
authors.affiliation: Medicine and Pharmacy Research Center, Binzhou Medical University, Yantai 264003, Shandong Province, China.
authors.forename: Qiang
authors.initials: Q
authors.lastname: Zhang
authors.affiliation: Medicine and Pharmacy Research Center, Binzhou Medical University, Yantai 264003, Shandong Province, China.
authors.forename: Xiaoyan
authors.initials: X
authors.lastname: Xu
authors.affiliation: Binzhou Medical University, Yantai 264003, Shandong Province, China.
authors.forename: Defang
authors.initials: D
authors.lastname: Li
authors.affiliation: Medicine and Pharmacy Research Center, Binzhou Medical University, Yantai 264003, Shandong Province, China. Electronic address: liminjing512@126.com.
authors.forename: Minjing
authors.initials: M
authors.lastname: Li
mesh_terms: D000818:Animals; D006528:Carcinoma, Hepatocellular / Q000235:genetics* / Q000473:pathology; D002392:Catechin / Q000008:administration & dosage / Q000031:analogs & derivatives; D002465:Cell Movement / Q000235:genetics; D049109:Cell Proliferation / Q000235:genetics; D004721:Endoplasmic Reticulum / Q000187:drug effects; D000091342:Endoplasmic Reticulum Chaperone BiP; D006360:Heat-Shock Proteins / Q000235:genetics*; D056945:Hep G2 Cells; D006801:Humans; D007334:Insulin-Like Growth Factor I / Q000235:genetics; D008113:Liver Neoplasms / Q000235:genetics* / Q000473:pathology; D019869:Phosphatidylinositol 3-Kinases / Q000235:genetics; D010766:Phosphorylation / Q000187:drug effects; D051057:Proto-Oncogene Proteins c-akt / Q000235:genetics; D017526:Receptor, IGF Type 1; D017451:Receptors, Somatomedin / Q000235:genetics*; D015398:Signal Transduction / Q000187:drug effects / Q000235:genetics
chemical_list: D002392:Catechin; D000091342:Endoplasmic Reticulum Chaperone BiP; D006360:Heat-Shock Proteins; D007334:Insulin-Like Growth Factor I; D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt; D017526:Receptor, IGF Type 1; D017451:Receptors, Somatomedin; C000717247:HSPA5 protein, human; C583557:IGF1 protein, human; C000597236:IGF1R protein, human; C057580:gallocatechol
keywords: GRP78; Hepatoma; IGF-IR; Signaling