title: Assessment of the effect of sphingosine kinase inhibitors on apoptosis,unfolded protein response and autophagy of T-cell acute lymphoblastic leukemia cells; indications for novel therapeutics.
abstract: Sphingosine 1-phosphate (S1P) is a bioactive lipid that is formed by the phosphorylation of sphingosine and catalysed by sphingosine kinase 1 (SK1) or sphingosine kinase 2 (SK2). Sphingosine kinases play a fundamental role in many signaling pathways associated with cancer, suggesting that proteins belonging to this signaling network represent potential therapeutic targets. Over the last years, many improvements have been made in the treatment of T-cell acute lymphoblastic leukemia (T-ALL); however, novel and less toxic therapies are still needed, especially for relapsing and chemo-resistant patients. Here, we analyzed the therapeutic potential of SKi and ROMe, a sphingosine kinase 1 and 2 inhibitor and SK2-selective inhibitor, respectively. While SKi induced apoptosis, ROMe initiated an autophagic cell death in our in vitro cell models. SKi treatment induced an increase in SK1 protein levels in Molt-4 cells, whereas it activated the endoplasmic reticulum (ER) stress/unfolded protein response (UPR) pathway in Jurkat and CEM-R cells as protective mechanisms in a sub-population of T-ALL cells. Interestingly, we observed a synergistic effect of SKi with the classical chemotherapeutic drug vincristine. In addition, we reported that SKi affected signaling cascades implicated in survival, proliferation and stress response of cells. These findings indicate that SK1 or SK2 represent potential targets for treating T-ALL.
authors.affiliation: Department of Biomedical and Neuromotor Sciences (DIBINEM), University of Bologna, Bologna, Italy.
authors.forename: Cecilia
authors.initials: C
authors.lastname: Evangelisti
authors.affiliation: Institute of Molecular Genetics, National Research Council-Rizzoli Orthopedic Institute, Bologna, Italy. Muscoloskeletal Cell Biology Laboratory, IOR, Bologna, Italy.
authors.forename: Camilla
authors.initials: C
authors.lastname: Evangelisti
authors.affiliation: Department of Biomedical and Neuromotor Sciences (DIBINEM), University of Bologna, Bologna, Italy.
authors.forename: Gabriella
authors.initials: G
authors.lastname: Teti
authors.affiliation: Institute of Molecular Genetics, National Research Council-Rizzoli Orthopedic Institute, Bologna, Italy. Muscoloskeletal Cell Biology Laboratory, IOR, Bologna, Italy.
authors.forename: Francesca
authors.initials: F
authors.lastname: Chiarini
authors.affiliation: Department of Biomedical and Neuromotor Sciences (DIBINEM), University of Bologna, Bologna, Italy.
authors.forename: Mirella
authors.initials: M
authors.lastname: Falconi
authors.affiliation: Pediatric Oncology and Hematology Unit 'Lalla Seragnoli', S. Orsola-Malpighi Hospital, University of Bologna, Bologna, Italy.
authors.forename: Fraia
authors.initials: F
authors.lastname: Melchionda
authors.affiliation: Pediatric Oncology and Hematology Unit 'Lalla Seragnoli', S. Orsola-Malpighi Hospital, University of Bologna, Bologna, Italy.
authors.forename: Andrea
authors.initials: A
authors.lastname: Pession
authors.affiliation: Oncoematologia Pediatrica, IRCCS Ospedale Pediatrico Bambino Gesù, Rome, Italy.
authors.forename: Alice
authors.initials: A
authors.lastname: Bertaina
authors.affiliation: Oncoematologia Pediatrica, IRCCS Ospedale Pediatrico Bambino Gesù, Rome, Italy.
authors.forename: Franco
authors.initials: F
authors.lastname: Locatelli
authors.affiliation: Department of Microbiology and Immunology, Brody School of Medicine, East Carolina University, Greenville, NC, USA.
authors.forename: James A
authors.initials: JA
authors.lastname: McCubrey
authors.affiliation: Department of Chemistry and Biochemistry, Queens College, The City University of New York, Flushing, New York, United States.
authors.forename: Dong Jae
authors.initials: DJ
authors.lastname: Beak
authors.affiliation: Department of Chemistry and Biochemistry, Queens College, The City University of New York, Flushing, New York, United States.
authors.forename: Robert
authors.initials: R
authors.lastname: Bittman
authors.affiliation: Strathclyde Institute of Pharmacy and Biomedical Sciences, University of Strathclyde, 161 Cathedral St, Glasgow, G4 0RE, Scotland, UK.
authors.forename: Susan
authors.initials: S
authors.lastname: Pyne
authors.affiliation: Strathclyde Institute of Pharmacy and Biomedical Sciences, University of Strathclyde, 161 Cathedral St, Glasgow, G4 0RE, Scotland, UK.
authors.forename: Nigel J
authors.initials: NJ
authors.lastname: Pyne
authors.affiliation: Department of Biomedical and Neuromotor Sciences (DIBINEM), University of Bologna, Bologna, Italy.
authors.forename: Alberto M
authors.initials: AM
authors.lastname: Martelli
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects*; D001343:Autophagy / Q000187:drug effects*; D015153:Blotting, Western; D045744:Cell Line, Tumor; D004791:Enzyme Inhibitors / Q000494:pharmacology; D000068876:Fingolimod Hydrochloride; D006801:Humans; D046529:Microscopy, Electron, Transmission; D017853:Phosphotransferases (Alcohol Group Acceptor) / Q000037:antagonists & inhibitors; D054218:Precursor T-Cell Lymphoblastic Leukemia-Lymphoma / Q000473:pathology*; D011409:Propylene Glycols / Q000494:pharmacology*; D013110:Sphingosine / Q000031:analogs & derivatives* / Q000494:pharmacology; D013844:Thiazoles / Q000494:pharmacology*; D056811:Unfolded Protein Response / Q000187:drug effects*; D000099157:Sphingosine Kinase
chemical_list: D000970:Antineoplastic Agents; D004791:Enzyme Inhibitors; D000068876:Fingolimod Hydrochloride; D017853:Phosphotransferases (Alcohol Group Acceptor); D011409:Propylene Glycols; D013110:Sphingosine; D013844:Thiazoles; D000099157:Sphingosine Kinase; C525025:4-(4-(4-chloro-phenyl)thiazol-2-ylamino)phenol