An Endogenous Mtor Inhibitor, Pras40, Is Upregulated In Lung Cancer And Contributes To Tumor Cell Invasion And Chemoresistance

The proline-rich Akt substrate of 40-kDa (PRAS40) has recently been identified as a regulatory component of, TORC1 (a complex composed of mTOR, GβL, DEPTOR, RAPTOR and PRAS40)Phosphorylation of Thr246 on PRAS40 by PKB/Akt, and Ser183 and Ser221 by mTOR results in the dissociation of PRAS40 from TORC1, and binding of PRAS40 to 14-3-3 proteins. Negative mTOR regulators usually play anti-tumorigenesis roles (like TSC1-TSC2, LKB1 and PTEN). Unexpectedly, PRAS40 has been shown to acted as a pro-tumorigenic factor in certain types of cancer cells. To better understand the role of PRAS40 in cancer, we have carried out a series of cell culture and patient tumor tissue based studies. Here, we report that PRAS40 was upregulated in most of the non-small cell lung cancer (NSCLC) cell lines examined when compared to normal lung epithelial cell lines. Further immonuhistochemistry (IHC) studies confirmed the overexpression of PRAS40 in tumor tissues from NSCLC patients. Significantly, nearly 60% of cancer tissues from NSCLC patients exhibited considerably higher levels of PRAS40 protein than those in paired normal lung tissue. Such high levels of PRAS40 expression appear to be required for tumor progression as silencing of PRAS40 by shRNA decreased the cell invasion ability of NSCLC cells. Subsequently, we investigated whether PRAS40 can influence the sensitivity of NSCLC cells to chemotharepitic drugs. Our data demonstrated that downregulation of PRAS40 protein increased the sensitivity of NSCLC cells to chemotherapeutic agents, such as etopside and perifosine. In summary, our results strongly support a pro-tumorigenic role for PRAS40 and suggest PRAS40 could be a potential NSCLC therapeutic target. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 112. doi:1538-7445.AM2012-112