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

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

doi:10.18632/oncotarget.11841

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.

Highlights

Cancer ranks among the leading causes of death worldwide [1]; this makes the development of novel and improved anti-cancer treatment a priority
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
By screening a variety of cancer cell lines for their ability to become more sensitive to genotoxins in the presence of TAT-RasGAP317-326, we found 13 tumor cell lines that were directly killed by the peptide (Table 1)

Summary

Introduction

Cancer ranks among the leading causes of death worldwide [1]; this makes the development of novel and improved anti-cancer treatment a priority. Cancer cells can adapt and become refractory to therapy by mutating and acquiring the ability to resist apoptotic stimuli [2]. Development of treatments able to trigger non-apoptotic forms of death in cancer cells is of prime interest. Regulated forms of cell death include the intensively studied apoptosis, necroptosis and autophagy and less known forms of death such as pyroptosis and parthanatos. These different types of cell death diverge at the level of the morphological changes and biochemical features triggered by death stimuli [4,5,6]

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