Sphingosine Kinase 1 Overexpression Contributes to Cetuximab Resistance in Human Colorectal Cancer Models(791 views) Rosa R, Marciano R, Malapelle U, Formisano L, Nappi L, D'Amato C, D'Amato V, Damiano V, Marf G, Del Vecchio S, Zannetti A, Greco A, De Stefano A, Carlomagno C, Veneziani BM, Troncone G, De Placido S, Bianco R
Clin Cancer Res (ISSN: 1078-0432, 1078-0432linking, 1078-0432print), 2013 Jan 1; 19(1): 138-147.
Keywords: Cetuximab, Fingolimod, N Dimethylsphingosine, Small Interfering Rna, Sphingosine Kinase 1, Animal Experiment, Animal Model, Animal Tissue, Apoptosis, Article, Cancer Cell Culture, Cancer Inhibition, Cancer Patient, Cancer Resistance, Cancer Tissue, Colorectal Cancer, Controlled Study, Drug Response, Drug Sensitivity, Enzyme Activation, Enzyme Inhibition, Gene Silencing, Human, Human Cell, Human Tissue, Immunohistochemistry, In Vitro Study, In Vivo Study, Mouse, Nonhuman, Nucleotide Sequence, Priority Journal, Protein Expression, Signal Transduction, Survival Time, Treatment Duration, Tumor Xenograft, Antibodies, Monoclonal, Humanized, Antineoplastic Agents, Cell Line, Colorectal Neoplasms, Disease Models, Drug Resistance, Gene Expression, Phosphotransferases (alcohol Group Acceptor), Propylene Glycols, Receptors, Lysosphingolipid, Treatment Outcome, Xenograft Model Antitumor Assays, Humanized Pharmacology Therapeutic Use, Antineoplastic Agents Pharmacology Therapeutic Use, Colorectal Neoplasms Drug Therapy Genetics Metabolism, Neoplasm Drug Effects Genetics, Phosphotransferases (alcohol Group Acceptor) Genetics Metabolism, Propylene Glycols Pharmacology, Lysosphingolipid Antagonists, Inhibitors, Sphingosine Analogs, Derivatives Pharmacology,
Affiliations: *** IBB - CNR ***
Cattedra di Oncologia Medica, Dipartimento di Endocrinologia e Oncologia Molecolare e Clinica, Universitàdi Napoli Federico II, Via S. Pansini, 5, 80131 Napoli, Italy
Scienze Biomorfologiche e Funzionali, Università di Napoli Federico II, Naples, Italy
Institute of Biostructures and Bioimages, National Research Council, Naples, Italy
CEINGE, Biotecnologie Avanzate, Naples, Italy
Dipartimento di Biologia e Patologia Cellulare e Molecolare L. Califano, Università di Napoli Federico II, Naples, Italy
Dipartimento di Medicina Sperimentale e Scienze Biochimiche, Università di Roma Tor Vergata, Rome, Italy
Dipartimenti di Endocrinologia ed Oncologia Molecolare e Clinica, Universita di Napoli Federico II, Napoli, Italy.
References: Not available.
Sphingosine Kinase 1 Overexpression Contributes to Cetuximab Resistance in Human Colorectal Cancer Models
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. Clin Cancer Res; 19(1); 138-47. (c) 2012 AACR.
Sphingosine Kinase 1 Overexpression Contributes to Cetuximab Resistance in Human Colorectal Cancer Models
Petraglia F, Singh AA, Carafa V, Nebbioso A, Conte M, Scisciola L, Valente S, Baldi A, Mandoli A, Petrizzi VB, Ingenito C, De Falco S, Cicatiello V, Apicella I, Janssen-megens EM, Kim B, Yi G, Logie C, Heath S, Ruvo M, Wierenga ATJ, Flicek P, Yaspo ML, Della Valle V, Bernard O, Tomassi S, Novellino E, Feoli A, Sbardella G, Gut I, Vellenga E, Stunnenberg HG, Mai A, Martens JHA, Altucci L * Combined HAT/EZH2 modulation leads to cancer-selective cell death(433 views) Oncotarget (ISSN: 1949-2553electronic, 1949-2553linking), 2018 May 22; 9(39): 25630-25646. Impact Factor:5.008 ViewExport to BibTeXExport to EndNote