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.
Highlights
Ligation of cancer cell surface GRP78 by activated ␣2-macroglobulin (␣2M*) promotes proliferation and blocks apoptosis
Fatty-acid Synthase or PI 3-Kinase/Akt/mTORC Signaling Pathway Inhibitors Suppress ␣2M* or Insulin-induced Protein and DNA Synthesis—We first assessed whether lipogenesis is involved in ␣2M*-induced cell proliferation by pretreating 1-LN and DU-145 cells with specific inhibitors of Akt1, mTORC1, mTORC2, or fatty-acid synthase, because these regulate cell proliferation by modulating SREBP processing and fatty-acid synthase activity
GRP78 is expressed on rheumatoid, but not normal, synovial fibroblasts [32], 1-LN and DU-145, but not PC-3 prostate cancer cells, and highly activated but not resident peritoneal macrophages
Summary
Ligation of cancer cell surface GRP78 by activated ␣2-macroglobulin (␣2M*) promotes proliferation and blocks 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. Growth factors play a role in the progression of these cancers by ligating cell surface-binding sites to induce receptor autophosphorylation at specific tyrosine residues. This results in the assembly of multiprotein complexes, which activate sig-
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
