title: Activated α2-macroglobulin binding to human prostate cancer cells triggers insulin-like responses.
abstract: Ligation of cell surface GRP78 by activated α2-macroglobulin (α2M*) promotes cell proliferation and suppresses apoptosis. α2M*-treated human prostate cancer cells exhibit a 2-3-fold increase in glucose uptake and lactate secretion, an effect similar to insulin treatment. In both α2M* and insulin-treated cells, the mRNA levels of SREBP1-c, SREBP2, fatty-acid synthase, acetyl-CoA carboxylase, ATP citrate lyase, and Glut-1 were significantly increased together with their protein levels, except for SREBP2. Pretreatment of cells with α2M* antagonist antibody directed against the carboxyl-terminal domain of GRP78 blocks these α2M*-mediated effects, and silencing GRP78 expression by RNAi inhibits up-regulation of ATP citrate lyase and fatty-acid synthase. α2M* induces a 2-3-fold increase in lipogenesis as determined by 6-[(14)C]glucose or 1-[(14)C]acetate incorporation into free cholesterol, cholesterol esters, triglycerides, free fatty acids, and phosphatidylcholine, which is blocked by inhibitors of fatty-acid synthase, PI 3-kinase, mTORC, or an antibody against the carboxyl-terminal domain of GRP78. We also assessed the incorporation of [(14)CH3]choline into phosphatidylcholine and observed similar effects. Lipogenesis is significantly affected by pretreatment of prostate cancer cells with fatostatin A, which blocks sterol regulatory element-binding protein proteolytic cleavage and activation. This study demonstrates that α2M* functions as a growth factor, leading to proliferation of prostate cancer cells by promoting insulin-like responses. An antibody against the carboxyl-terminal domain of GRP78 may have important applications in prostate cancer therapy.
authors.affiliation: From the Department of Pathology, Duke University Medical Center, Durham, North Carolina 27710.
authors.forename: Uma Kant
authors.initials: UK
authors.lastname: Misra
authors.affiliation: From the Department of Pathology, Duke University Medical Center, Durham, North Carolina 27710 salvatore.pizzo@duke.edu.
authors.forename: Salvatore Vincent
authors.initials: SV
authors.lastname: Pizzo
mesh_terms: D000912:Antibodies, Neoplasm / Q000276:immunology / Q000494:pharmacology; D015153:Blotting, Western; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects*; D002784:Cholesterol / Q000378:metabolism; D000091342:Endoplasmic Reticulum Chaperone BiP; D054890:Fatty Acid Synthase, Type I / Q000235:genetics / Q000378:metabolism; D015870:Gene Expression / Q000187:drug effects; D005947:Glucose / Q000378:metabolism*; D006360:Heat-Shock Proteins / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D006801:Humans; D007004:Hypoglycemic Agents / Q000494:pharmacology; D007328:Insulin / Q000494:pharmacology*; D007773:Lactates / Q000378:metabolism; D050356:Lipid Metabolism / Q000187:drug effects / Q000235:genetics; D050155:Lipogenesis / Q000187:drug effects / Q000235:genetics; D008297:Male; D011471:Prostatic Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D011485:Protein Binding; D020133:Reverse Transcriptase Polymerase Chain Reaction; D051780:Sterol Regulatory Element Binding Protein 1 / Q000235:genetics / Q000378:metabolism; D000511:alpha-Macroglobulins / Q000378:metabolism / Q000494:pharmacology*
chemical_list: D000912:Antibodies, Neoplasm; D000091342:Endoplasmic Reticulum Chaperone BiP; C000717247:HSPA5 protein, human; D006360:Heat-Shock Proteins; D007004:Hypoglycemic Agents; D007328:Insulin; D007773:Lactates; D051780:Sterol Regulatory Element Binding Protein 1; D000511:alpha-Macroglobulins; D002784:Cholesterol; C518729:FASN protein, human; D054890:Fatty Acid Synthase, Type I; D005947:Glucose
keywords: Aerobic Glycolysis; Antibody Directed Against the Carboxyl-terminal Domain of GRP78; Cell Surface GRP78; Glycolysis; Lipogenesis; Prostate Cancer; Signal Transduction; Warburg Effect; α-2-Macroglobulin and Metabolic Regulation