The TAT-RasGAP317-326 anti-cancer peptide can kill in a caspase-, apoptosis-, and necroptosis-independent manner
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Mathieu Heulot1,*, Nadja Chevalier1,*, Julien Puyal2, Christiane Margue3, Sébastien Michel1, Stephanie Kreis3, Dagmar Kulms4,5, David Barras6, Aimable Nahimana7, Christian Widmann1
1Department of Physiology, University of Lausanne, Lausanne, Switzerland
2Department of Fundamental Neurosciences, University of Lausanne, Lausanne, Switzerland
3Signal Transduction Laboratory, Life Sciences Research Unit, University of Luxembourg, Luxembourg, Luxembourg
4Experimental Dermatology, Department of Dermatology, TU-Dresden, Dresden, Germany
5Center for Regenerative Therapies, TU-Dresden, Dresden, Germany
6Bioinformatics Core Facility, Swiss Institute of Bioinformatics, Lausanne, Switzerland
7Service and Central Laboratory of Hematology, University Hospital of Lausanne, Lausanne, Switzerland
*These authors have contributed equally to this work
Christian Widmann, email: [email protected]
Keywords: tumor cell death, non-apoptotic death, cell-permeable peptides, RasGAP
Received: April 21, 2016 Accepted: August 24, 2016 Published: September 02, 2016
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-RasGAP317-326, 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-RasGAP317-326 can cause cell death in a manner that can be either partially caspase-dependent or fully caspase-independent. Indeed, TAT-RasGAP317-326-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-RasGAP317-326 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.
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