Purpose. Although the anti-Epidermal Growth Factor (EGFR) monoclonal antibody (mAb) 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 signalling 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 (DMS) 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 re-sensitization to cetuximab both in vitro and in vivo, with significant inhibition of tumor growth, interference with signal transduction, induction of cancer cells apoptosis and prolongation of mice survival. Finally, immunohistochemical analysis on colorectal cancer tissues revealed a correlation between SphK1 expression and cetuximab response. Conclusion. Our data could contribute to clarify SphK1 role in cetuximab resistance and may suggest SphK1 inhibition as a part of novel targeting strategies potentially effective also in resistant colorectal cancer patients.

Sphingosine Kinase 1 (SphK1) overespression contributes to cetuximab resistance in human colrectal cancer / Rosa, Roberta; Marciano, M.; Malapelle, Umberto; Formisano, Luigi; Nappi, Lucia; D'Amato, C.; D'Amato, V.; Damiano, Vincenzo; Marfe, G.; DEL VECCHIO, Silvana; Zannetti, A.; Greco, Adelaide; DE STEFANO, Alfonso; Carlomagno, Chiara; Veneziani, BIANCA MARIA; Troncone, Giancarlo; DE PLACIDO, Sabino; Bianco, Roberto. - In: CLINICAL CANCER RESEARCH. - ISSN 1557-3265. - 19:1(2013), pp. 138-147. [10.1158/1078-0432.CCR-12-1050]

Sphingosine Kinase 1 (SphK1) overespression contributes to cetuximab resistance in human colrectal cancer.

ROSA, ROBERTA;MALAPELLE, UMBERTO;FORMISANO, LUIGI;NAPPI, LUCIA;DAMIANO, VINCENZO;DEL VECCHIO, SILVANA;GRECO, ADELAIDE;DE STEFANO, ALFONSO;CARLOMAGNO, Chiara;VENEZIANI, BIANCA MARIA;TRONCONE, GIANCARLO;DE PLACIDO, SABINO;BIANCO, ROBERTO
2013

Abstract

Purpose. Although the anti-Epidermal Growth Factor (EGFR) monoclonal antibody (mAb) 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 signalling 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 (DMS) 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 re-sensitization to cetuximab both in vitro and in vivo, with significant inhibition of tumor growth, interference with signal transduction, induction of cancer cells apoptosis and prolongation of mice survival. Finally, immunohistochemical analysis on colorectal cancer tissues revealed a correlation between SphK1 expression and cetuximab response. Conclusion. Our data could contribute to clarify SphK1 role in cetuximab resistance and may suggest SphK1 inhibition as a part of novel targeting strategies potentially effective also in resistant colorectal cancer patients.
2013
Sphingosine Kinase 1 (SphK1) overespression contributes to cetuximab resistance in human colrectal cancer / Rosa, Roberta; Marciano, M.; Malapelle, Umberto; Formisano, Luigi; Nappi, Lucia; D'Amato, C.; D'Amato, V.; Damiano, Vincenzo; Marfe, G.; DEL VECCHIO, Silvana; Zannetti, A.; Greco, Adelaide; DE STEFANO, Alfonso; Carlomagno, Chiara; Veneziani, BIANCA MARIA; Troncone, Giancarlo; DE PLACIDO, Sabino; Bianco, Roberto. - In: CLINICAL CANCER RESEARCH. - ISSN 1557-3265. - 19:1(2013), pp. 138-147. [10.1158/1078-0432.CCR-12-1050]
File in questo prodotto:
File Dimensione Formato  
Sfingosina_CCR2012.pdf

solo utenti autorizzati

Tipologia: Documento in Post-print
Licenza: Accesso privato/ristretto
Dimensione 6.65 MB
Formato Adobe PDF
6.65 MB Adobe PDF   Visualizza/Apri   Richiedi una copia

I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.

Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/11588/519846
Citazioni
  • ???jsp.display-item.citation.pmc??? ND
  • Scopus 91
  • ???jsp.display-item.citation.isi??? 85
social impact