iTorin1—An Active Site Inhibitor of mTOR, Suppresses Prostate Cancer Cell Growth Induced by Activated α2M-Macroglobulin Ligation of Cell Surface GRP78

In this study, we reported the effect of the ATP binding site competitive inhibitor Torin1 on activated α₂-macroglobulin (α₂M*)-induced cell proliferation and activation of mTORC1 and mTORC2 signaling in prostate cancer cells. Torin1 significantly inhibited α₂M*-induced cellproliferation as measured by protein and DNA synthesis. Translational activity, a major cellular response in malignant cells,is coordinately regulated by the mTORC1-S6-kinaseand mTORC1-4EBP1 axes. Torin1 significantly inhibited α₂M*- and insulin-induced activation of mTORC1 as determined by phosphorylation of S6-kinaseat Thr³⁸⁹ and 4EBP1 at Thr^37/46 compared to untreated cells employing Raptor immunoprecipitates. Torin1 also significantly inhibited α₂M*- and insulin-induced upregulation of p-Akt^T308 and p-Akt^S473 in prostate cancer cells. The effect was comparable to that of insulin employed as a positive control. Finally, Torin1 inhibited α₂M*- and insulin-induced activation of mTORC2 kinase assayas measured by phosphorylation of Akt at Ser⁴⁷³ inRictor immunoprecipitates of prostate cancer cells.

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