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

// Cecilia Evangelisti 1 , Camilla Evangelisti 2,3 , Gabriella Teti 1 , Francesca Chiarini 2,3 , Mirella Falconi 1 , Fraia Melchionda 4 , Andrea Pession 4 , Alice Bertaina 5 , Franco Locatelli 5 , James A. McCubrey 6 , Dong Jae Beak 7 , Robert Bittman 7 , Susan Pyne 8 , Nigel J. Pyne 8 and Alberto M. Martelli 1 1 Department of Biomedical and Neuromotor Sciences (DIBINEM), University of Bologna, Bologna, Italy 2 Institute of Molecular Genetics, National Research Council-Rizzoli Orthopedic Institute, Bologna, Italy 3 Muscoloskeletal Cell Biology Laboratory, IOR, Bologna, Italy 4 Pediatric Oncology and Hematology Unit ‘Lalla Seragnoli’, S. Orsola-Malpighi Hospital, University of Bologna, Bologna, Italy 5 Oncoematologia Pediatrica, IRCCS Ospedale Pediatrico Bambino Gesù, Rome, Italy 6 Department of Microbiology and Immunology, Brody School of Medicine, East Carolina University, Greenville, NC, USA 7 Department of Chemistry and Biochemistry, Queens College, The City University of New York, Flushing, New York, United States 8 Strathclyde Institute of Pharmacy and Biomedical Sciences, University of Strathclyde, 161 Cathedral St, Glasgow, G4 0RE, Scotland, UK Correspondence: Alberto M. Martelli, email: // Keywords : T-cell acute lymphoblastic leukemia, sphingosine kinase inhibitors, apoptosis, autophagy, unfolded protein response Received : June 24, 2014 Accepted : August 05, 2014 Published : August 06, 2014 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.