A Fhit-mimetic peptide suppresses annexin A4-mediated chemoresistance to paclitaxel in lung cancer cells

// Eugenio Gaudio 1,2,3,* , Francesco Paduano 3,* , Apollinaire Ngankeu 1 , Francesco Ortuso 4 , Francesca Lovat 1 , Sandra Pinton 2 , Sabrina D’Agostino 3 , Nicola Zanesi 1 , Rami I. Aqeilan 1,5 , Pietro Campiglia 6 , Ettore Novellino 7 , Stefano Alcaro 4 , Carlo M. Croce 1 and Francesco Trapasso 3 1 Department of Molecular Immunology, Virology and Medical Genetics, The Ohio State University, Columbus, Ohio, USA 2 Lymphoma & Genomics Research Program, IOR Institute of Oncology Research, Bellinzona, Switzerland 3 Dipartimento di Medicina Sperimentale e Clinica, University Magna Graecia, Campus “S. Venuta”, Catanzaro, Italy 4 Dipartimento di Scienze della Salute, University Magna Graecia, Campus “S. Venuta”, Catanzaro, Italy 5 The Lautenberg Center for Immunology and Cancer Research, Institute for Medical Research, The Hebrew University, Jerusalem, Israel 6 Dipartimento di Farmacia, Universita di Salerno, Fisciano, Italy 7 Dipartimento di Farmacia, Universita degli Studi di Napoli “Federico II”, Napoli, Italy * These authors have contributed equally to this work Correspondence to: Carlo M. Croce, email: // Francesco Trapasso, email: // Keywords : fragile histidine triad, FHIT, annexin A4, ANXA4, mimetic peptides Received : January 07, 2016 Accepted : April 11, 2016 Published : May 04, 2016 Abstract We recently reported that Fhit is in a molecular complex with annexin A4 (ANXA4); following to their binding, Fhit delocalizes ANXA4 from plasma membrane to cytosol in paclitaxel-resistant lung cancer cells, thus restoring their chemosensitivity to the drug. Here, we demonstrate that Fhit physically interacts with A4 through its N-terminus; molecular dynamics simulations were performed on a 3D Fhit model to rationalize its mechanism of action. This approach allowed for the identification of the QHLIKPS heptapeptide (position 7 to 13 of the wild-type Fhit protein) as the smallest Fhit sequence still able to preserve its ability to bind ANXA4. Interestingly, Fhit peptide also recapitulates the property of the native protein in inhibiting Annexin A4 translocation from cytosol to plasma membrane in A549 and Calu-2 lung cancer cells treated with paclitaxel. Finally, the combination of Tat-Fhit peptide and paclitaxel synergistically increases the apoptotic rate of cultured lung cancer cells and blocks in vivo tumor formation. Our findings address to the identification of chemically simplified Fhit derivatives that mimic Fhit tumor suppressor functions; intriguingly, this approach might lead to the generation of novel anticancer drugs to be used in combination with conventional therapies in Fhit-negative tumors to prevent or delay chemoresistance.