Oncotarget

Research Papers:

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

Mathieu Heulot _, Nadja Chevalier, Julien Puyal, Christiane Margue, Sébastien Michel, Stephanie Kreis, Dagmar Kulms, David Barras, Aimable Nahimana and Christian Widmann

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Oncotarget. 2016; 7:64342-64359. https://doi.org/10.18632/oncotarget.11841

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Abstract

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

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-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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