Activated {alpha}2-Macroglobulin Binding to Human Prostate Cancer Cells Triggers Insulin-like Responses [Cell Biology]

February 26th, 2015 by Misra, U. K., Pizzo, S. V.

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-Co-A 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 upregulation 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 phosphatidyl choline, 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 phosphatidyl choline and observed similar effects. Lipogenesis is significantly affected by pre-treatment of prostate cancer cells with fatostatin A, which blocks SREBP proteolytic cleavage and activation. The present 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.