Inhibition of mTORC2 component RICTOR impairs tumor growth in pancreatic cancer models
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Katharina M. Schmidt1, Claus Hellerbrand2, Petra Ruemmele3, Christoph W. Michalski4, Bo Kong5, Alexander Kroemer1, Christina Hackl1, Hans J. Schlitt1, Edward K. Geissler1, Sven A. Lang1,6
1Department of Surgery, University Hospital Regensburg, Regensburg, Germany
2Department of Internal Medicine I, University Hospital Regensburg, Germany
3Department of Pathology, Hospital of Erlangen, Erlangen, Germany
4Department of Surgery, University of Heidelberg, Germany
5Department of Surgery, Technische Universität München (TUM), Munich, Germany
6Department of Surgery, Universität Freiburg, Freiburg, Germany
Sven A. Lang, email: [email protected]
Keywords: mTORC2/RICTOR, PDAC, AKT, HIF-1
Received: September 12, 2016 Accepted: February 06, 2017 Published: February 20, 2017
Mammalian Target of Rapamycin complex 2 (mTORC2) and its regulatory component Rapamycin-insensitive companion of mTOR (RICTOR) are increasingly recognized as important players in human cancer development and progression. However, the role of RICTOR in human pancreatic ductal adenocarcinoma (PDAC) is unclear so far. Here, we sought to analyze the effects of RICTOR inhibition in human pancreatic cancer cell lines in vitro and in vivo. Furthermore, RICTOR expression was determined in human PDAC samples. Results demonstrate that depletion of RICTOR with siRNA (transient knock-down) or shRNA (stable knock-down) has an inhibitory effect on tumor growth in vitro. Moreover, RICTOR inhibition led to impaired phosphorylation/activity of AGC kinases (AKT, SGK1). Interestingly, hypoxia-induced expression of hypoxia-induced factor-1α (HIF-1α) was diminished and secretion of vascular-endothelial growth factor-A (VEGF-A) was impaired upon targeting RICTOR. Stable RICTOR knock-down led to significant inhibition of tumor growth in subcutaneous and orthotopic tumor models which was accompanied by significant reduction of tumor cell proliferation. Finally, immunohistochemical analyses of 85 human PDAC samples revealed significantly poorer survival in patients with higher RICTOR expression. In conclusion, these findings provide first evidence for mTORC2/RICTOR as an attractive novel target for treatment of human PDAC.
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