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.
Department of Physiology, University of Lausanne, Lausanne, Switzerland.
Mathieu
M
Heulot
Department of Physiology, University of Lausanne, Lausanne, Switzerland.
Nadja
N
Chevalier
Department of Fundamental Neurosciences, University of Lausanne, Lausanne, Switzerland.
Julien
J
Puyal
Signal Transduction Laboratory, Life Sciences Research Unit, University of Luxembourg, Luxembourg, Luxembourg.
Christiane
C
Margue
Department of Physiology, University of Lausanne, Lausanne, Switzerland.
Sébastien
S
Michel
Signal Transduction Laboratory, Life Sciences Research Unit, University of Luxembourg, Luxembourg, Luxembourg.
Stephanie
S
Kreis
Experimental Dermatology, Department of Dermatology, TU-Dresden, Dresden, Germany.|Center for Regenerative Therapies, TU-Dresden, Dresden, Germany.
Dagmar
D
Kulms
Bioinformatics Core Facility, Swiss Institute of Bioinformatics, Lausanne, Switzerland.
David
D
Barras
Service and Central Laboratory of Hematology, University Hospital of Lausanne, Lausanne, Switzerland.
Aimable
A
Nahimana
Department of Physiology, University of Lausanne, Lausanne, Switzerland.
Christian
C
Widmann
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D061945:Caspase Inhibitors / Q000494:pharmacology; D020169:Caspases / Q000235:genetics / Q000378:metabolism*; D045744:Cell Line, Tumor; D002522:Chlorocebus aethiops; D004305:Dose-Response Relationship, Drug; D005260:Female; D020690:GTPase-Activating Proteins / Q000494:pharmacology*; D057809:HEK293 Cells; D006801:Humans; D008297:Male; D009336:Necrosis; D009369:Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D010446:Peptide Fragments / Q000494:pharmacology*; D015398:Signal Transduction / Q000187:drug effects; D013997:Time Factors; D014709:Vero Cells
D000970:Antineoplastic Agents; D061945:Caspase Inhibitors; D020690:GTPase-Activating Proteins; D010446:Peptide Fragments; C525242:TAT-RasGAP(317-326); D020169:Caspases
RasGAP; cell-permeable peptides; non-apoptotic death; tumor cell death