Activated α2-Macroglobulin Binding to Human Prostate Cancer Cells Triggers Insulin-like Responses

• Published in: The Journal of biological chemistry 2015-04, Vol.290 (15), p.9571-9587
• Main Authors: Misra, Uma Kant, Pizzo, Salvatore Vincent
• Format: Article
• Language: English
• Subjects: Aerobic Glycolysis; alpha-Macroglobulins - metabolism; alpha-Macroglobulins - pharmacology; Antibodies, Neoplasm - immunology; Antibodies, Neoplasm - pharmacology; Antibody Directed Against the Carboxyl-terminal Domain of GRP78; Blotting, Western; Cell Line, Tumor; Cell Proliferation - drug effects; Cell Surface GRP78; Cholesterol - metabolism; Fatty Acid Synthase, Type I - genetics; Fatty Acid Synthase, Type I - metabolism; Gene Expression - drug effects; Glucose - metabolism; Glycolysis; Heat-Shock Proteins - genetics; Heat-Shock Proteins - immunology; Heat-Shock Proteins - metabolism; Humans; Hypoglycemic Agents - pharmacology; Insulin - pharmacology; Lactates - metabolism; Lipid Metabolism - drug effects; Lipid Metabolism - genetics; Lipogenesis; Lipogenesis - drug effects; Lipogenesis - genetics; Male; Prostate Cancer; Prostatic Neoplasms - genetics; Prostatic Neoplasms - metabolism; Prostatic Neoplasms - pathology; Protein Binding; Reverse Transcriptase Polymerase Chain Reaction; Signal Transduction; Sterol Regulatory Element Binding Protein 1 - genetics; Sterol Regulatory Element Binding Protein 1 - metabolism; Warburg Effect; α-2-Macroglobulin and Metabolic Regulation
• ISSN: 0021-9258; 1083-351X
• DOI: 10.1074/jbc.M114.617837

Background: Ligation of cancer cell surface GRP78 by activated α2-macroglobulin (α2M*) promotes proliferation and blocks apoptosis. Results: α2M* treatment of prostate cancer cells enhances the Warburg effect and up-regulates lipid metabolism in an insulin-like manner. Conclusion: α2M* exerts insulin-like effects on prostate cancer cells. Significance: Targeting cell surface GRP78-dependent cancer cell regulation, such as by antibodies, offers a unique potential therapeutic approach. 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-[14C]glucose or 1-[14C]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 [14CH3]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.