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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.

SUBMITTER: Evangelisti C

PROVIDER: S-EPMC4202168 | biostudies-literature | 2014 Sep

REPOSITORIES: biostudies-literature

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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.

Evangelisti Cecilia C Evangelisti Camilla C Teti Gabriella G Chiarini Francesca F Falconi Mirella M Melchionda Fraia F Pession Andrea A Bertaina Alice A Locatelli Franco F McCubrey James A JA Beak Dong Jae DJ Bittman Robert R Pyne Susan S Pyne Nigel J NJ Martelli Alberto M AM

Oncotarget 20140901 17

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); howev ...[more]

PMID: 25226616

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Project description:T‑cell acute lymphoblastic leukemia (T‑ALL) is a common pediatric malignancy, characterized by the abnormal presence of immature T‑cell progenitors. Conventional treatments for T‑ALL fail to prevent or cure the disease, with a high‑risk of recurrence after the first remission. Thus, medical options are in demand to develop novel therapies for patients suffering with T‑ALL. Niclosamide, a traditional oral anti‑helminthic drug, has been reported to be a potential anticancer agent that regulates intracellular signaling pathways. Few studies have yet investigated the effects of niclosamide on the development of T‑ALL. Here, the present study aimed to investigate the anti‑leukemia effects of niclosamide on T‑ALL. We first hypothesized that the suppressive effects of niclosamide on the tumor growth of T‑ALL are exerted by regulating autophagy and apoptosis. Following niclosamide treatment, T‑ALL cell viability was evaluated using MTT assay, and apoptosis with Annexin V/propidium iodide staining. In T‑ALL cells treated with niclosamide, changes in apoptosis‑ and autophagy‑related proteins were analyzed by western blotting. In addition, in an in vivo model, T‑ALL xenograft mice were used to study the anti‑leukemia effects of niclosamide. The results showed that niclosamide significantly reduced the viability of Jurkat and CCRF‑CEM T‑ALL cells in both a dose‑ and time‑dependent manner. Niclosamide significantly activated the early and late phases of apoptosis in Jurkat (at 2 µM) and CCRF‑CEM cells (at 1 µM). Furthermore, niclosamide upregulated protein expression of cleaved caspase‑3 and LC3B, while downregulated those of Bcl‑2 and p62, in a dose‑dependent manner in both Jurkat and CCRF‑CEM cells. The in vivo results showed that niclosamide treatment significantly suppressed tumor growth and the disease progression in T‑ALL xenograft mice by activating cleaved caspase‑3 and LC3B. We conclude that niclosamide plays an anti‑leukemia role, and that it represents a novel approach for the treatment of T‑ALL.

Dataset Information

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.

Publications

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.

Similar Datasets

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