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

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.