Author(s)

Uma K. Misra, Salvatore V. Pizzo

Department of Pathology, Duke University Medical Center, Durham, UK.

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.

α₂-Macroglobulin; Torin1; Prostate Cancer Cells Proliferation; p-S6K^T389; p-4EBP1; p-Akt^S473; Insulin

U. Misra and S. Pizzo, "iTorin1—An Active Site Inhibitor of mTOR, Suppresses Prostate Cancer Cell Growth Induced by Activated α2M-Macroglobulin Ligation of Cell Surface GRP78," Journal of Cancer Therapy, Vol. 4 No. 4A, 2013, pp. 74-85. doi: 10.4236/jct.2013.44A008.