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

Eugenio Gaudio, Francesco Paduano, Apollinaire Ngankeu, Francesco Ortuso, Francesca Lovat, Sandra Pinton, Sabrina D'Agostino, Nicola Zanesi, Rami I. Aqeilan, Pietro Campiglia, Ettore Novellino, Stefano Alcaro, Carlo M. Croce*, Francesco Trapasso

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

16 Scopus citations


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 eptapeptide (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 inhinibiting 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.

Original languageAmerican English
Pages (from-to)29927-29936
Number of pages10
Issue number21
StatePublished - 24 May 2016

Bibliographical note

Funding Information:
This work was supported by AIRC (Associazione Italiana Ricerca Cancro) (F.T.) and NIH grant CA152758 (C.M.C.).


  • ANXA4
  • Annexin A4
  • FHIT
  • Fragile histidine triad
  • Mimetic peptides


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