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Inhibition of sphingosine kinase 1 enhances cytotoxicity, ceramide levels and ROS formation in liver cancer cells treated with selenite
Stockholm University, Faculty of Science, Department of Genetics, Microbiology and Toxicology.
Karolinska Institutet.
Karolinska Institutet.
Karolinska Institutet.
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2012 (English)In: Biochemical Pharmacology, ISSN 0006-2952, E-ISSN 1356-1839, Vol. 84, no 5, 712-721 p.Article in journal (Refereed) Published
Abstract [en]

High doses of selenite have been shown to induce cell death in acute myeloid leukemia and lung cancercells. In this study, we combined selenite treatment with modulators of sphingolipid metabolism in thehepatocellular carcinoma cell line Huh7. Treatment with 20 mM of selenite reduced the viability of Huh7cells by half and increased the levels of long chain C14-, C16-, C18- and C18:1- ceramides by two-fold.Inhibition of neutral sphingomyelinase with 3-O-methylsphingosine significantly reduced the cytotoxiceffect of selenite. In line with this result, selenite caused a 2.5-fold increase in the activity of neutralsphingomyelinase. The sphingosine kinase 1 (SK1) inhibitor 2-(p-hydroxyanilino)-4-(p-chlorophe-nyl)thiazole (SK1-II) sensitized the cells to the cytotoxic effects of selenite. Preincubation with 10 mM ofSK1-II prior to treatment with 10 mM of selenite caused induction of apoptosis and gave rise to a 2.5-foldincrease in C14-, C16-, C18- and C18:1- ceramides. Instead, 50 mM of SK1-II combined with 10 mM ofselenite caused accumulation of cells in G1/S phases, but less apoptosis and accumulation of ceramides.The formation of reactive oxygen species (ROS) after treatment with 10 mM of selenite was maximallyenhanced by 1 mM of SK1-II. Moreover, combined treatment with SK1-II and 10 mM of selenitesynergistically reduced the number of viable Huh7 cells, while the non-tumorigenic hepatocyte cell lineMIHA remained unaffected by the same treatment. These results raise the possibility that a combinationof selenite and SK1 inhibitors could be used to treat liver cancer cells, that are regarded as drug resistant,at doses that are non-toxic to normal liver cells.

Place, publisher, year, edition, pages
2012. Vol. 84, no 5, 712-721 p.
Keyword [en]
sphingosine kinase 1, ceramide, selenite, cytotoxicity, cancer, ROS
National Category
Biological Sciences
Research subject
Molecular Genetics
Identifiers
URN: urn:nbn:se:su:diva-79012DOI: 10.1016/j.bcp.2012.06.009ISI: 000307435700014OAI: oai:DiVA.org:su-79012DiVA: diva2:546573
Available from: 2012-08-24 Created: 2012-08-23 Last updated: 2017-12-07Bibliographically approved
In thesis
1. Studies of bioactive lipids in cancer
Open this publication in new window or tab >>Studies of bioactive lipids in cancer
2012 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Lipids are a broad class of molecules that, besides being a major form of energy storage and components of cell membranes, act as bioactive signalling molecules. N-acyl taurines are structurally related to endocannabinoids that are known to exert antiproliferative actions in a variety of cancer cells. We have evaluated the cytotoxicity of N-oleoyl taurine and N-arachidonoyl taurine and found N-acyl taurines to reduce proliferation of prostate cancer cells.

The sphingolipids ceramide and sphingosine act as tumour suppressors. We found selenite treatment to cause reduced viability, induction of neutral sphingomyelinase activity and accumulation of ceramide in the liver cancer cells. Inhibition of sphingosine kinase 1 (SK1) sensitized the cells to selenite treatment with regards to ceramide accumulation, arrest of cells in the G1/S phases of the cell cycle and formation of reactive oxygen species. Whereas combined selenite treatment and SK1 inhibition synergistically reduced the number of viable cells, the non-tumorigenic hepatocyte cell line, remained unaffected.

Furthermore, we studied the involvement of sphingolipid metabolism in bladder cancer cells treated with Bacillus Calmette-Guérin (BCG), and found BCG to induce formation of nitric oxide and upregulation of nitric oxide synthase 2 as well as SK1 protein levels. Additionally, pharmacological inhibition of SK1 enhanced the viability reduction, ceramide accumulation and induction of apoptosis observed following BCG treatment.

In conclusion, our findings have shown that N-acyl taurines exert antiproliferative effects on prostate cancer cells. Furthermore, sphingolipids were shown to be involved in cytotoxic treatment with selenite and BCG in liver cancer and bladder cancer cells respectively, and inhibition of SK1 increased the cytotoxicity. Our findings raise the possibility that modulation of ceramide-metabolizing enzymes could be used to enhance the effects of selenite and BCG in these cancer cell types.

Place, publisher, year, edition, pages
Stockholm: Department of Genetics, Microbiology and Toxicology, Stockholm University, 2012. 67 p.
Keyword
Lipids, Sphingolipids, N-acyl amino acids, cancer
National Category
Biological Sciences
Research subject
Molecular Genetics
Identifiers
urn:nbn:se:su:diva-79024 (URN)978-91-7447-548-7 (ISBN)
Public defence
2012-09-26, lecture room G, Arrheniuslaboratorierna, Svante Arrhenius väg 20 C, Stockholm, 13:00 (English)
Opponent
Supervisors
Note

At the time of the doctoral defense, the following papers were unpublished and had a status as follows: Paper 3: Manuscript. Paper 4: Manuscript.

Available from: 2012-09-04 Created: 2012-08-23 Last updated: 2012-08-27Bibliographically approved

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