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Bacillus Calmette-Guérin treatment specifically induces SK1 protein expression inurothelial bladder-cancer cells
Stockholm University, Faculty of Science, Department of Genetics, Microbiology and Toxicology.
Karolinska Institutet.
Karolinska Institutet.
Karolinska Institutet.
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(English)Manuscript (preprint) (Other academic)
Abstract [en]

Bladder instillation with Bacillus Calmétte-Guerin (BCG) is an established treatmentmodality for superficial high-risk urinary bladder-cancer and carcinoma in situ (CIS), but theanti-tumor mechanisms following BCG-instillations remain largely unknown. In this study weexamined the effects of BCG-treatment on SK1 protein expression in the murine bladdercancer cell line MBT2. To simulate in vivo BCG-instillations, where the immune systemplays a vital role for successful BCG-treatment, we also stimulated MBT2 cells withsupernatant from BCG-treated (SupBCG) or un-treated Raw 264.7 macrophages. BCGtreatment as well as SupBCG treatment induced SK1 protein expression. Treatment with thesphingosine-kinase 1 (SK1) inhibitor 2-(p-hydroxyanilino)-4-(p-chlorophenyl)thiazole (SK1-II) induced reduced viability in a dose dependent manner. However, combined treatment withBCG diminished this viability reduction suggesting a protective effect of BCG, but not ofSup-BCG, from SK1-II induced toxicity. Apoptosis was detected, as PARP-cleavage, in cellstreated with SupBCG whereas BCG-only or supernatant from untreated macrophages did notinduce apoptosis. A substantial increase in ceramides C18, C18:1 and C20:1 was observedafter BCG-treatment. These ceramide subspecies, as well as ceramides C14, C16, C20, C22and C22:1, were also induced by 20 or 30M of SK1-II, but the induction was abrogated byco-treatement with BCG. Following treatment with Sup-BCG, the levels of all the abovementioned ceramide subspecies were increased. Levels of ceramides C14, C16, C18, C18:1,C20, C20:1, C22 and C22:1 were more than two times higher in response to combinedtreatment with Sup-BCG and 10M of SK1-II as compared to treatment with Sup-BCG orSK1-II alone. Taken together these data suggest the sphingolipid metabolism as an importantpathway in the response to BCG-therapy.

Keyword [en]
Bacillus Calmétte-Guerin, Bladder cancer, carcinoma in situ
National Category
Medical and Health Sciences
Research subject
Molecular Genetics
Identifiers
URN: urn:nbn:se:su:diva-79015OAI: oai:DiVA.org:su-79015DiVA: diva2:546580
Available from: 2012-08-24 Created: 2012-08-23 Last updated: 2012-08-27Bibliographically 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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