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| Content Provider | World Health Organization (WHO)-Global Index Medicus |
|---|---|
| Author | Pizzo, Salvatore Vincent Misra, Uma Kant |
| Description | Author Affiliation: Misra UK ( From the Department of Pathology, Duke University Medical Center, Durham, North Carolina 27710.); Pizzo SV ( From the Department of Pathology, Duke University Medical Center, Durham, North Carolina 27710 salvatore.pizzo@duke.edu.) |
| Abstract | Ligation of cell surface GRP78 by activated 2-macroglobulin ( 2M*) promotes cell proliferation and suppresses apoptosis. 2M*-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 2M* 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 2M* antagonist antibody directed against the carboxyl-terminal domain of GRP78 blocks these 2M*-mediated effects, and silencing GRP78 expression by RNAi inhibits up-regulation of ATP citrate lyase and fatty-acid synthase. 2M* 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 2M* 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. |
| ISSN | 00219258 |
| e-ISSN | 1083351X |
| Journal | Journal of Biological Chemistry |
| Issue Number | 15 |
| Volume Number | 290 |
| Language | English |
| Publisher | American Society for Biochemistry and Molecular Biology (United States) |
| Publisher Date | 2015-04-10 |
| Publisher Place | United States |
| Access Restriction | Open |
| Subject Keyword | Cell Proliferation Drug Effects Glucose Metabolism Insulin Pharmacology Alpha-Macroglobulins Antibodies, Neoplasm Immunology Blotting, Western Cell Line, Tumor Cholesterol Fatty Acid Synthase, Type I Genetics Gene Expression Heat-Shock Proteins Hypoglycemic Agents Lactates Lipid Metabolism Lipogenesis Prostatic Neoplasms Pathology Protein Binding Reverse Transcriptase Polymerase Chain Reaction Sterol Regulatory Element Binding Protein 1 Biochemistry Molecular Biology |
| Content Type | Text |
| Resource Type | Article |
| Subject | Cell Biology Biochemistry Molecular Biology |
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