Sphingosine kinase 1 overexpression contributes to cetuximab resistance in human colorectal cancer models

Roberta Rosa, Roberta Marciano, Umberto Malapelle, Luigi Formisano, Lucia Nappi, Claudia D'Amato, Valentina D'Amato, Vincenzo Damiano, Gabriella Marfè, Silvana Del Vecchio, Antonella Zannetti, Adelaide Greco, Alfonso De Stefano, Chiara Carlomagno, Bianca Maria Veneziani, Giancarlo Troncone, Sabino De Placido, Roberto Bianco

Research output: Contribution to journalArticlepeer-review

Abstract

Purpose: Although the anti-EGF receptor (EGFR) monoclonal antibody cetuximab is an effective strategy in colorectal cancer therapy, its clinical use is limited by intrinsic or acquired resistance. Alterations in the "sphingolipid rheostat" - the balance between the proapoptotic molecule ceramide and the mitogenic factor sphingosine-1-phosphate (S1P) - due to sphingosine kinase 1 (SphK1) overactivation have been involved in resistance to anticancer-targeted agents. Moreover, cross-talks between SphK1 and EGFR-dependent signaling pathways have been described. Experimental design: We investigated SphK1 contribution to cetuximab resistance in colorectal cancer, in preclinical in vitro /in vivo models, and in tumor specimens from patients. Results: SphK1 was found overexpressed and overactivated in colorectal cancer cells with intrinsic or acquired resistance to cetuximab. SphK1 contribution to resistance was supported by the demonstration that SphK1 inhibition by N,N -dimethyl-sphingosine or silencing via siRNA in resistant cells restores sensitivity to cetuximab, whereas exogenous SphK1 overexpression in sensitive cells confers resistance to these agents. Moreover, treatment of resistant cells with fingolimod (FTY720), a S1P receptor (S1PR) antagonist, resulted in resensitization to cetuximab both in vitro and in vivo, with inhibition of tumor growth, interference with signal transduction, induction of cancer cells apoptosis, and prolongation of mice survival. Finally, a correlation between SphK1 expression and cetuximab response was found in colorectal cancer patients.

Original languageEnglish
Pages (from-to)138-147
Number of pages10
JournalClinical Cancer Research
Volume19
Issue number1
DOIs
Publication statusPublished - Jan 1 2013

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

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