Binding of doxorubicin to Sorcin impairs cell death and increases drug resistance in cancer cells

Silvia Masciarelli, Ilaria Genovese, Annarita Fiorillo, Andrea Ilari, Francesco Fazi, Gianni Colotti

Risultato della ricerca: Contributo in rivistaArticolo in rivista

26 Citazioni (Scopus)

Abstract

Sorcin is a calcium binding protein that plays an important role in multidrug resistance (MDR) in tumors, since its expression confers resistance to doxorubicin and to other chemotherapeutic drugs. In this study, we show that Sorcin is able to bind doxorubicin, vincristine, paclitaxel and cisplatin directly and with high affinity. The high affinity binding of doxorubicin to sorcin has been demonstrated with different techniques, that is, surface plasmon resonance, fluorescence titration and X-ray diffraction. Although the X-ray structure of sorcin in complex with doxorubicin has been solved at low resolution, it allows the identification of one of the two doxorubicin binding sites, placed at the interface between the EF5 loop the G helix and the EF4 loop. We show that Sorcin cellular localization changes upon doxorubicin treatment, an indication that the protein responds to doxorubicin and it presumably binds the drug also inside the cell, soon after drug entrance. We also demonstrate that Sorcin is able to limit the toxic effects of the chemotherapeutic agent in the cell. In addition, Sorcin silencing increases cell death upon treatment with doxorubicin, increases the accumulation of doxorubicin in cell nucleus, decreases the expression of MDR1 and doxorubicin efflux via MDR1.
Lingua originaleEnglish
pagine (da-a)e2950-N/A
RivistaCELL DEATH & DISEASE
Volume8
DOI
Stato di pubblicazionePubblicato - 2017

Keywords

  • A549 Cells
  • ATP Binding Cassette Transporter, Subfamily B
  • Calcium-Binding Proteins
  • Cell Death
  • Crystallography, X-Ray
  • Doxorubicin
  • Drug Resistance, Multiple
  • Drug Resistance, Neoplasm
  • HeLa Cells
  • Humans
  • Neoplasm Proteins
  • Neoplasms
  • Protein Binding
  • Protein Structure, Secondary

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