title: Sphingosine kinase 1 overexpression contributes to cetuximab resistance in human colorectal cancer models.
abstract: OBJECTIVE
  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.
  
  
  METHODS
  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.
authors.affiliation: Dipartimenti di Endocrinologia ed Oncologia Molecolare e Clinica, Università di Napoli Federico II, Napoli, Italy.
authors.forename: Roberta
authors.initials: R
authors.lastname: Rosa
authors.forename: Roberta
authors.initials: R
authors.lastname: Marciano
authors.forename: Umberto
authors.initials: U
authors.lastname: Malapelle
authors.forename: Luigi
authors.initials: L
authors.lastname: Formisano
authors.forename: Lucia
authors.initials: L
authors.lastname: Nappi
authors.forename: Claudia
authors.initials: C
authors.lastname: D'Amato
authors.forename: Valentina
authors.initials: V
authors.lastname: D'Amato
authors.forename: Vincenzo
authors.initials: V
authors.lastname: Damiano
authors.forename: Gabriella
authors.initials: G
authors.lastname: Marfè
authors.forename: Silvana
authors.initials: S
authors.lastname: Del Vecchio
authors.forename: Antonella
authors.initials: A
authors.lastname: Zannetti
authors.forename: Adelaide
authors.initials: A
authors.lastname: Greco
authors.forename: Alfonso
authors.initials: A
authors.lastname: De Stefano
authors.forename: Chiara
authors.initials: C
authors.lastname: Carlomagno
authors.forename: Bianca Maria
authors.initials: BM
authors.lastname: Veneziani
authors.forename: Giancarlo
authors.initials: G
authors.lastname: Troncone
authors.forename: Sabino
authors.initials: S
authors.lastname: De Placido
authors.forename: Roberto
authors.initials: R
authors.lastname: Bianco
mesh_terms: D000818:Animals; D061067:Antibodies, Monoclonal, Humanized / Q000494:pharmacology* / Q000627:therapeutic use; D000970:Antineoplastic Agents / Q000494:pharmacology* / Q000627:therapeutic use; D045744:Cell Line, Tumor; D000068818:Cetuximab; D015179:Colorectal Neoplasms / Q000188:drug therapy / Q000235:genetics* / Q000378:metabolism; D004195:Disease Models, Animal; D019008:Drug Resistance, Neoplasm / Q000187:drug effects / Q000235:genetics; D000068876:Fingolimod Hydrochloride; D015870:Gene Expression; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D017853:Phosphotransferases (Alcohol Group Acceptor) / Q000235:genetics* / Q000378:metabolism; D011409:Propylene Glycols / Q000494:pharmacology; D049349:Receptors, Lysosphingolipid / Q000037:antagonists & inhibitors; D013110:Sphingosine / Q000031:analogs & derivatives / Q000494:pharmacology; D000081025:Sphingosine-1-Phosphate Receptors; D016896:Treatment Outcome; D023041:Xenograft Model Antitumor Assays; D000099157:Sphingosine Kinase
chemical_list: D061067:Antibodies, Monoclonal, Humanized; D000970:Antineoplastic Agents; D000068818:Cetuximab; D000068876:Fingolimod Hydrochloride; D017853:Phosphotransferases (Alcohol Group Acceptor); D011409:Propylene Glycols; D049349:Receptors, Lysosphingolipid; D013110:Sphingosine; D000081025:Sphingosine-1-Phosphate Receptors; D000099157:Sphingosine Kinase; C477362:S1PR1 protein, human