The TAT-RasGAP317-326 anti-cancer peptide can kill in a caspase-, apoptosis-, and necroptosis-independent manner

Abstract

// Mathieu Heulot 1, * , Nadja Chevalier 1, * , Julien Puyal 2 , Christiane Margue 3 , Sébastien Michel 1 , Stephanie Kreis 3 , Dagmar Kulms 4, 5 , David Barras 6 , Aimable Nahimana 7 , Christian Widmann 1 1 Department of Physiology, University of Lausanne, Lausanne, Switzerland 2 Department of Fundamental Neurosciences, University of Lausanne, Lausanne, Switzerland 3 Signal Transduction Laboratory, Life Sciences Research Unit, University of Luxembourg, Luxembourg, Luxembourg 4 Experimental Dermatology, Department of Dermatology, TU-Dresden, Dresden, Germany 5 Center for Regenerative Therapies, TU-Dresden, Dresden, Germany 6 Bioinformatics Core Facility, Swiss Institute of Bioinformatics, Lausanne, Switzerland 7 Service and Central Laboratory of Hematology, University Hospital of Lausanne, Lausanne, Switzerland * These authors have contributed equally to this work Correspondence to: Christian Widmann, email: Christian.Widmann@unil.ch Keywords: tumor cell death, non-apoptotic death, cell-permeable peptides, RasGAP Received: April 21, 2016     Accepted: August 24, 2016     Published: September 02, 2016 ABSTRACT Tumor cell resistance to apoptosis, which is triggered by many anti-tumor therapies, remains a major clinical problem. Therefore, development of more efficient therapies is a priority to improve cancer prognosis. We have previously shown that a cell-permeable peptide derived from the p120 Ras GTPase-activating protein (RasGAP), called TAT-RasGAP 317-326 , bears anti-malignant activities in vitro and in vivo , such as inhibition of metastatic progression and tumor cell sensitization to cell death induced by various anti-cancer treatments. Recently, we discovered that this RasGAP-derived peptide possesses the ability to directly kill some cancer cells. TAT-RasGAP 317-326 can cause cell death in a manner that can be either partially caspase-dependent or fully caspase-independent. Indeed, TAT-RasGAP 317-326 -induced toxicity was not or only partially prevented when apoptosis was inhibited. Moreover, blocking other forms of cell death, such as necroptosis, parthanatos, pyroptosis and autophagy did not hamper the killing activity of the peptide. The death induced by TAT-RasGAP 317-326 can therefore proceed independently from these modes of death. Our finding has potentially interesting clinical relevance because activation of a death pathway that is distinct from apoptosis and necroptosis in tumor cells could lead to the generation of anti-cancer drugs that target pathways not yet considered for cancer treatment.