Faculty Opinions recommendation of Overexpression of sphingosine-1-phosphate lyase or inhibition of sphingosine kinase in Dictyostelium discoideum results in a selective increase in sensitivity to platinum-based chemotherapy drugs.

ABSTRACT The efficacy of the chemotherapy drug cisplatin is often limited due to resistance of the tumors to the drug, and increasing the potency of cisplatin without increasing its concentration could prove beneficial. A previously characterized Dictyostelium discoideum mutant with increased resistance to cisplatin was defective in the gene encoding sphingosine-1-phosphate (S-1-P) lyase, which catalyzes the breakdown of S-1-P, an important regulatory molecule in cell function and development and in the regulation of cell fate. We hypothesized that the increased resistance to cisplatin was due to an elevation of S-1-P and predicted that lowering levels of S-1-P should increase sensitivity to the drug. We generated three strains that stably overexpress different levels of the S-1-P lyase. The overexpressor strains have reduced growth rate and, confirming the hypothesis, showed an expression-dependent increase in sensitivity to cisplatin. Consistently, treating the cells with d-erythro-N,N,-dimethylsphingosine, a known inhibitor of sphingosine kinase, increased the sensitivity of mutant and parent cells to cisplatin, while addition of exogenous S-1-P or 8-Br-cyclic AMP made the cells more resistant to cisplatin. The increased sensitivity of the overexpressors to cisplatin was also observed with the cisplatin analog carboplatin. In contrast, the response to doxorubicin, 5-flurouracil, or etoposide was unaffected, indicating that the involvement of the sphingolipid metabolic pathway in modulating the response to cisplatin is not part of a global genotoxic stress response. The augmented sensitivity to cisplatin appears to be the result of an intracellular signaling function of S-1-P, because D. discoideum does not appear to have endothelial differentiation growth (EDG/S1P) receptors. Overall, the results show that modulation of the sphingolipid pathway at multiple points can result in increased sensitivity to cisplatin and has the potential for increasing the clinical usefulness of this important drug.

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Sphingosine Kinase Regulates the Sensitivity of Dictyostelium discoideum Cells to the Anticancer Drug Cisplatin

Eukaryotic Cell ◽

10.1128/ec.4.1.178-189.2005 ◽

2005 ◽

Vol 4 (1) ◽

pp. 178-189 ◽

Cited By ~ 23

Author(s):

Junxia Min ◽

David Traynor ◽

Andrew L. Stegner ◽

Lei Zhang ◽

Marie H. Hanigan ◽

...

Keyword(s):

Dictyostelium Discoideum ◽

Drug Targets ◽

Sphingosine Kinase ◽

Biochemical Properties ◽

Sphingosine 1 Phosphate ◽

Sphingosine Kinases ◽

Cisplatin Sensitivity ◽

Increased Sensitivity ◽

Tumor Types ◽

Null Mutants

ABSTRACT The drug cisplatin is widely used to treat a number of tumor types. However, resistance to the drug, which remains poorly understood, limits its usefulness. Previous work using Dictyostelium discoideum as a model for studying drug resistance showed that mutants lacking sphingosine-1-phosphate (S-1-P) lyase, the enzyme that degrades S-1-P, had increased resistance to cisplatin, whereas mutants overexpressing the enzyme were more sensitive to the drug. S-1-P is synthesized from sphingosine and ATP by the enzyme sphingosine kinase. We have identified two sphingosine kinase genes in D. discoideum—sgkA and sgkB—that are homologous to those of other species. The biochemical properties of the SgkA and SgkB enzymes suggest that they are the equivalent of the human Sphk1 and Sphk2 enzymes, respectively. Disruption of the kinases by homologous recombination (both single and double mutants) or overexpression of the sgkA gene resulted in altered growth rates and altered response to cisplatin. The null mutants showed increased sensitivity to cisplatin, whereas mutants overexpressing the sphingosine kinase resulted in increased resistance compared to the parental cells. The results indicate that both the SgkA and the SgkB enzymes function in regulating cisplatin sensitivity. The increase in sensitivity of the sphingosine kinase-null mutants was reversed by the addition of S-1-P, and the increased resistance of the sphingosine kinase overexpressor mutant was reversed by the inhibitor N,N-dimethylsphingosine. Parallel changes in sensitivity of the null mutants are seen with the platinum-based drug carboplatin but not with doxorubicin, 5-fluorouracil, and etoposide. This pattern of specificity is similar to that observed with the S-1-P lyase mutants and should be useful in designing therapeutic schemes involving more than one drug. This study identifies the sphingosine kinases as new drug targets for modulating the sensitivity to platinum-based drugs.

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Faculty Opinions recommendation of Sphingosine kinase regulates the sensitivity of Dictyostelium discoideum cells to the anticancer drug cisplatin.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.1002523.296723 ◽

2005 ◽

Author(s):

Richard Gomer

Keyword(s):

Dictyostelium Discoideum ◽

Anticancer Drug ◽

Sphingosine Kinase

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Apoptotic cell extrusion depends on single-cell synthesis of sphingosine-1-phosphate by sphingosine kinase 2

Biochimica et Biophysica Acta (BBA) - Molecular and Cell Biology of Lipids ◽

10.1016/j.bbalip.2021.158888 ◽

2021 ◽

Vol 1866 (4) ◽

pp. 158888

Author(s):

Bruno Jaime Santacreu ◽

Daniela Judith Romero ◽

Lucila Gisele Pescio ◽

Estefanía Tarallo ◽

Norma Beatriz Sterin-Speziale ◽

...

Keyword(s):

Single Cell ◽

Apoptotic Cell ◽

Sphingosine Kinase ◽

Sphingosine Kinase 2 ◽

Sphingosine 1 Phosphate ◽

Cell Synthesis ◽

Cell Extrusion

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An audit of UK audiological practice in specialist paediatric oncology centres regarding hearing assessment of children at risk of ototoxicity due to chemotherapy

The Journal of Laryngology & Otology ◽

10.1017/s0022215121000025 ◽

2021 ◽

Vol 135 (1) ◽

pp. 14-20

Author(s):

E C M Brown ◽

C Caimino ◽

C L Benton ◽

D M Baguley

Keyword(s):

High Frequency ◽

Good Practice ◽

Paediatric Oncology ◽

Chemotherapy Drugs ◽

Team Working ◽

Platinum Based Chemotherapy ◽

Hearing Assessment ◽

Self Test ◽

The Uk ◽

Monitoring Service

AbstractObjectivePlatinum-based chemotherapy drugs are associated with substantial ototoxicity. The hearing of children treated with these drugs should be closely monitored.MethodA questionnaire was sent out to the 19 audiology departments associated with national paediatric cancer specialist centres in the UK looking at current practice in ototoxicity monitoring.ResultsResponses were received from 17 of 19 centres (89 per cent). All offered some form of audiometric monitoring service. Extended high-frequency testing (9–20 kHz) was only utilised by 7 services (29 per cent). A majority of respondents were reluctant to consider self-test devices in paediatric ototoxicity monitoring (n = 9; 53 per cent). Provision of long-term audiological follow up is sporadic with only 4 (23 per cent) respondents keeping all children with normal hearing under review once treatment is completed.ConclusionWhile some good practice in paediatric ototoxicity was identified, opportunities exist to improve clinical practice and protocols, promote multidisciplinary team working and to utilise technologies such as extended high frequency and self-test audiometry.

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The control of the balance between ceramide and sphingosine-1-phosphate by sphingosine kinase: Oxidative stress and the seesaw of cell survival and death

Comparative Biochemistry and Physiology Part B Biochemistry and Molecular Biology ◽

10.1016/j.cbpb.2012.05.006 ◽

2012 ◽

Vol 163 (1) ◽

pp. 26-36 ◽

Cited By ~ 117

Author(s):

James R. Van Brocklyn ◽

Joseph B. Williams

Keyword(s):

Oxidative Stress ◽

Cell Survival ◽

Sphingosine Kinase ◽

Sphingosine 1 Phosphate

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Mice Deficient in Sphingosine Kinase 1 Are Rendered Lymphopenic by FTY720

Journal of Biological Chemistry ◽

10.1074/jbc.m406512200 ◽

2004 ◽

Vol 279 (50) ◽

pp. 52487-52492 ◽

Cited By ~ 339

Author(s):

Maria L. Allende ◽

Teiji Sasaki ◽

Hiromichi Kawai ◽

Ana Olivera ◽

Yide Mi ◽

...

Keyword(s):

Vascular Development ◽

Sphingosine Kinase ◽

Sphingosine Kinase 1 ◽

Cellular Functions ◽

Lymphocyte Trafficking ◽

Signaling Molecule ◽

Physiological Functions ◽

Sphingosine 1 Phosphate ◽

Sphingosine Kinases ◽

S1p Receptor

Sphingosine-1-phosphate (S1P), a lipid signaling molecule that regulates many cellular functions, is synthesized from sphingosine and ATP by the action of sphingosine kinase. Two such kinases have been identified, SPHK1 and SPHK2. To begin to investigate the physiological functions of sphingosine kinase and S1P signaling, we generated mice deficient in SPHK1.Sphk1null mice were viable, fertile, and without any obvious abnormalities. Total SPHK activity in mostSphk1-/-tissues was substantially, but not completely, reduced indicating the presence of multiple sphingosine kinases. S1P levels in most tissues from theSphk1-/- mice were not markedly decreased. In serum, however, there was a significant decrease in the S1P level. Although S1P signaling regulates lymphocyte trafficking, lymphocyte distribution was unaffected in lymphoid organs ofSphk1-/- mice. The immunosuppressant FTY720 was phosphorylated and elicited lymphopenia in theSphk1null mice showing that SPHK1 is not required for the functional activation of this sphingosine analogue prodrug. The results with theseSphk1null mice reveal that some key physiologic processes that require S1P receptor signaling, such as vascular development and proper lymphocyte distribution, can occur in the absence of SPHK1.

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Sphingosine kinase 2 prevents the nuclear translocation of sphingosine 1-phosphate receptor-2 and tyrosine 416 phosphorylated c-Src and increases estrogen receptor negative MDA-MB-231 breast cancer cell growth: The role of sphingosine 1-phosphate receptor-4

Cellular Signalling ◽

10.1016/j.cellsig.2014.01.023 ◽

2014 ◽

Vol 26 (5) ◽

pp. 1040-1047 ◽

Cited By ~ 17

Author(s):

Jan Ohotski ◽

Hugh Rosen ◽

Robert Bittman ◽

Susan Pyne ◽

Nigel J. Pyne

Keyword(s):

Breast Cancer ◽

Estrogen Receptor ◽

Nuclear Translocation ◽

Sphingosine Kinase ◽

Cancer Cell Growth ◽

Breast Cancer Cell Growth ◽

Sphingosine Kinase 2 ◽

Sphingosine 1 Phosphate ◽

Estrogen Receptor Negative

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Sphingosine Kinase as a Regulator of Calcium Entry through Autocrine Sphingosine 1-Phosphate Signaling in Thyroid FRTL-5 Cells

Endocrinology ◽

10.1210/en.2009-0288 ◽

2009 ◽

Vol 150 (11) ◽

pp. 5125-5134 ◽

Cited By ~ 11

Author(s):

Dan Gratschev ◽

Christoffer Löf ◽

Jari Heikkilä ◽

Anders Björkbom ◽

Pramod Sukumaran ◽

...

Keyword(s):

Intracellular Signaling ◽

Sphingosine Kinase ◽

Calcium Entry ◽

Dominant Negative ◽

Dependent Manner ◽

Concentration Dependent Manner ◽

Entry Pathway ◽

Sphingosine 1 Phosphate ◽

S1p Receptor ◽

In Cells

Calcium entry is one of the main regulators of intracellular signaling. Here, we have described the importance of sphingosine, sphingosine kinase 1 (SK1), and sphingosine 1-phosphate (S1P) in regulating calcium entry in thyroid FRTL-5 cells. In cells incubated with the phosphatase inhibitor calyculin A, which evokes calcium entry without mobilizing sequestered intracellular calcium, sphingosine inhibited calcium entry in a concentration-dependent manner. Furthermore, inhibiting SK1 or the ATP-binding cassette ABCC1 multidrug transporter attenuated calcium entry. The addition of exogenous S1P restored calcium entry. Neither sphingosine nor inhibition of SK1 attenuated thapsigargin-evoked calcium entry. Blocking S1P receptor 2 or phospholipase C attenuated calcium entry, whereas blocking S1P receptor 3 did not. Overexpression of wild-type SK1, but not SK2, enhanced calyculin-evoked calcium entry compared with mock-transfected cells, whereas calcium entry was decreased in cells transfected with the dominant-negative G82D SK1 mutant. Exogenous S1P restored calcium entry in G82D cells. Our results suggest that the calcium entry pathway is blocked by sphingosine and that activation of SK1 and the production of S1P, through an autocrine mechanism, facilitate calcium entry through activation of S1P receptor 2. This is a novel mechanism by which the sphingosine-S1P rheostat regulates cellular calcium homeostasis.

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