title: A Fhit-mimetic peptide suppresses annexin A4-mediated chemoresistance to paclitaxel in lung cancer cells.
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.
authors.affiliation: Department of Molecular Immunology, Virology and Medical Genetics, The Ohio State University, Columbus, Ohio, USA.|Lymphoma & Genomics Research Program, IOR Institute of Oncology Research, Bellinzona, Switzerland.|Dipartimento di Medicina Sperimentale e Clinica, University Magna Græcia, Campus "S. Venuta", Catanzaro, Italy.
authors.forename: Eugenio
authors.initials: E
authors.lastname: Gaudio
authors.affiliation: Dipartimento di Medicina Sperimentale e Clinica, University Magna Græcia, Campus "S. Venuta", Catanzaro, Italy.
authors.forename: Francesco
authors.initials: F
authors.lastname: Paduano
authors.affiliation: Department of Molecular Immunology, Virology and Medical Genetics, The Ohio State University, Columbus, Ohio, USA.
authors.forename: Apollinaire
authors.initials: A
authors.lastname: Ngankeu
authors.affiliation: Dipartimento di Scienze della Salute, University Magna Græcia, Campus "S. Venuta", Catanzaro, Italy.
authors.forename: Francesco
authors.initials: F
authors.lastname: Ortuso
authors.affiliation: Department of Molecular Immunology, Virology and Medical Genetics, The Ohio State University, Columbus, Ohio, USA.
authors.forename: Francesca
authors.initials: F
authors.lastname: Lovat
authors.affiliation: Lymphoma & Genomics Research Program, IOR Institute of Oncology Research, Bellinzona, Switzerland.
authors.forename: Sandra
authors.initials: S
authors.lastname: Pinton
authors.affiliation: Dipartimento di Medicina Sperimentale e Clinica, University Magna Græcia, Campus "S. Venuta", Catanzaro, Italy.
authors.forename: Sabrina
authors.initials: S
authors.lastname: D'Agostino
authors.affiliation: Department of Molecular Immunology, Virology and Medical Genetics, The Ohio State University, Columbus, Ohio, USA.
authors.forename: Nicola
authors.initials: N
authors.lastname: Zanesi
authors.affiliation: Department of Molecular Immunology, Virology and Medical Genetics, The Ohio State University, Columbus, Ohio, USA.|The Lautenberg Center for Immunology and Cancer Research, Institute for Medical Research, The Hebrew University, Jerusalem, Israel.
authors.forename: Rami I
authors.initials: RI
authors.lastname: Aqeilan
authors.affiliation: Dipartimento di Farmacia, Università di Salerno, Fisciano, Italy.
authors.forename: Pietro
authors.initials: P
authors.lastname: Campiglia
authors.affiliation: Dipartimento di Farmacia, Università degli Studi di Napoli "Federico II", Napoli, Italy.
authors.forename: Ettore
authors.initials: E
authors.lastname: Novellino
authors.affiliation: Dipartimento di Scienze della Salute, University Magna Græcia, Campus "S. Venuta", Catanzaro, Italy.
authors.forename: Stefano
authors.initials: S
authors.lastname: Alcaro
authors.affiliation: Department of Molecular Immunology, Virology and Medical Genetics, The Ohio State University, Columbus, Ohio, USA.
authors.forename: Carlo M
authors.initials: CM
authors.lastname: Croce
authors.affiliation: Dipartimento di Medicina Sperimentale e Clinica, University Magna Græcia, Campus "S. Venuta", Catanzaro, Italy.
authors.forename: Francesco
authors.initials: F
authors.lastname: Trapasso
mesh_terms: D000072283:A549 Cells; D017766:Acid Anhydride Hydrolases / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D017314:Annexin A4 / Q000378:metabolism*; D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology* / Q000627:therapeutic use; D002462:Cell Membrane / Q000378:metabolism; D019008:Drug Resistance, Neoplasm / Q000187:drug effects*; D005260:Female; D016147:Genes, Tumor Suppressor; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000235:genetics; D051379:Mice; D008819:Mice, Nude; D009363:Neoplasm Proteins / Q000235:genetics / Q000378:metabolism*; D017239:Paclitaxel / Q000494:pharmacology* / Q000627:therapeutic use; D010446:Peptide Fragments / Q000378:metabolism / Q000494:pharmacology* / Q000627:therapeutic use; D011485:Protein Binding; D021381:Protein Transport; D023041:Xenograft Model Antitumor Assays; D000099170:Bis(5'-adenosyl)triphosphatase
chemical_list: D017766:Acid Anhydride Hydrolases; D017314:Annexin A4; D000972:Antineoplastic Agents, Phytogenic; D009363:Neoplasm Proteins; D017239:Paclitaxel; D010446:Peptide Fragments; D000099170:Bis(5'-adenosyl)triphosphatase
keywords: ANXA4; FHIT; annexin A4; fragile histidine triad; mimetic peptides