Specific Targeting of Caspase-9/PP2A Interaction as Potential New Anti-Cancer Therapy - Sorbonne Université Accéder directement au contenu
Article Dans Une Revue PLoS ONE Année : 2013

Specific Targeting of Caspase-9/PP2A Interaction as Potential New Anti-Cancer Therapy

Issam Arrouss
  • Fonction : Auteur
  • PersonId : 918677
Marie Wislez
  • Fonction : Auteur
  • PersonId : 989590
Karim Dorgham
David Vallerand
  • Fonction : Auteur
  • PersonId : 955394
Nathalie Rabbe
  • Fonction : Auteur
Jerónimo Bravo
  • Fonction : Auteur
  • PersonId : 981974
Dominique Mazier
  • Fonction : Auteur
  • PersonId : 840106
Angelita Rebollo

Résumé

Purpose: PP2A is a serine/threonine phosphatase critical to physiological processes, including apoptosis. Cell penetrating peptides are molecules that can translocate into cells without causing membrane damage. Our goal was to develop cell-penetrating fusion peptides specifically designed to disrupt the caspase-9/PP2A interaction and evaluate their therapeutic potential in vitro and in vivo. Experimental Design: We generated a peptide containing a penetrating sequence associated to the interaction motif between human caspase-9 and PP2A (DPT-C9h), in order to target their association. Using tumour cell lines, primary human cells and primary human breast cancer (BC) xenografts, we investigated the capacity of DPT-C9h to provoke apoptosis in vitro and inhibition of tumour growth (TGI) in vivo. DPT-C9h was intraperitonealy administered at doses from 1 to 25 mg/kg/day for 5 weeks. Relative Tumour Volume (RTV) was calculated. Results: We demonstrated that DPT-C9h specifically target caspase-9/PP2A interaction in vitro and in vivo and induced caspase-9-dependent apoptosis in cancer cell lines. DPT-C9h also induced significant TGI in BC xenografts models. The mouse-specific peptide DPT-C9 also induced TGI in lung (K-Ras model) and breast cancer (PyMT) models. DPT-C9h has a specific effect on transformed B cells isolated from chronic lymphocytic leukemia patients without any effect on primary healthy cells. Finally, neither toxicity nor immunogenic responses were observed. Conclusion: Using the cell-penetrating peptides blocking caspase-9/PP2A interactions, we have demonstrated that DPT-C9h had a strong therapeutic effect in vitro and in vivo in mouse models of tumour progression.

Domaines

Cancer
Fichier principal
Vignette du fichier
journal.pone.0060816.PDF (1.47 Mo) Télécharger le fichier
Origine : Publication financée par une institution
Loading...

Dates et versions

hal-01534831 , version 1 (08-06-2017)

Licence

Paternité

Identifiants

Citer

Issam Arrouss, Fariba Némati, Fernando Roncal, Marie Wislez, Karim Dorgham, et al.. Specific Targeting of Caspase-9/PP2A Interaction as Potential New Anti-Cancer Therapy. PLoS ONE, 2013, 8 (4), pp.e60816. ⟨10.1371/journal.pone.0060816⟩. ⟨hal-01534831⟩
496 Consultations
189 Téléchargements

Altmetric

Partager

Gmail Facebook X LinkedIn More