Abstract
Protein phosphatase 2A (PP2A) is known to be a negative regulator of several survival and proliferating pathways that are frequently altered in cancer. In addition to chemical enzymatic inhibitors of the PP2A activity, the oncoprotein SET has been described as a physiological PP2A inhibitor by forming a complex with PP2A catalytic subunit (PP2Ac). Increased SET protein levels therefore directly reduce the tumor suppressor function of PP2A and promote tumor progression. We have used the PEP-Scan approach to identify the binding site between the serine/threonine phosphatase PP2A and the oncoprotein SET. For in vivo validation of the peptides, we have used chronic lymphocytic leukemia (CLL) xenograft models. In this manuscript we describe the identification of amino acid sequences involved in the complex formation, both at the PP2Ac and SET sides. The amino acid sequences of the binding sites were coupled to an optimized penetrating peptide in order to generate chimeras (Mut3DPT-PP2A and Mut3DPT-SET) able to target the PP2A/SET interaction. We demonstrate that these peptides have an in vitro apoptotic effect on breast and lung cancer cell lines, as well as an antitumoral effect on CLL and lymphoma xenograft models. The new generated chimeric peptides allow the modulation of the PP2Ac/SET interaction and might have a potential as a new therapeutic approach for cancer treatment.
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Acknowledgements
We thank Valerie Friser for help in the collection of the CLL samples. This work was supported by Inserm and SATT Lutech, the Belgian Foundation against Cancer (FAF-F/2016/822), the Fund for Scientific Research-Flanders (G.0B01.16N), the Belgian IAP Program (P7/13) and the KU Leuven (OT/13/094).
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All procedures performed in studies involving human participants were in accordance with the ethical standards of the National Ministry of Health and APHP committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards. Informed consent was obtained from all individual participants included in the study.
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All mice were maintained under conditions and protocols in accordance with the Directive 2010/63/UE of the Council of Europe on Animal Welfare. The studies (number authorization 5220) were approved by the French Ethics Committee for animal experimentation number 74 and all experiments were conducted following the guidelines of the aforementioned committee.
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Tian, L., Zhang, X., Haesen, D. et al. Identification of PP2A/Set Binding Sites and Design of Interacting Peptides with Potential Clinical Applications. Int J Pept Res Ther 24, 479–488 (2018). https://doi.org/10.1007/s10989-017-9633-1
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DOI: https://doi.org/10.1007/s10989-017-9633-1