Ceramide Kinase Is Upregulated in Metastatic Breast Cancer Cells and Contributes to Migration and Invasion by Activation of PI 3-Kinase and Akt.

Schwalm, Stephanie; Erhardt, Martin; Römer, Isolde; Pfeilschifter, Josef; Zangemeister-Wittke, Uwe; Huwiler, Andrea (2020). Ceramide Kinase Is Upregulated in Metastatic Breast Cancer Cells and Contributes to Migration and Invasion by Activation of PI 3-Kinase and Akt. International journal of molecular sciences, 21(4) Molecular Diversity Preservation International MDPI 10.3390/ijms21041396

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Ceramide kinase (CerK) is a lipid kinase that converts the proapoptotic ceramide to ceramide 1-phosphate, which has been proposed to have pro-malignant properties and regulate cell responses such as proliferation, migration, and inflammation. We used the parental human breast cancer cell line MDA-MB-231 and two single cell progenies derived from lung and bone metastasis upon injection of the parental cells into immuno-deficient mice. The lung and the bone metastatic cell lines showed a marked upregulation of CerK mRNA and activity when compared to the parental cell line. The metastatic cells also had increased migratory and invasive activity, which was dose-dependently reduced by the selective CerK inhibitor NVP-231. A similar reduction of migration was seen when CerK was stably downregulated with small hairpin RNA (shRNA). Conversely, overexpression of CerK in parental MDA-MB-231 cells enhanced migration, and this effect was also observed in the non-metastatic cell line MCF7 upon CerK overexpression. On the molecular level, CerK overexpression increased the activation of protein kinase Akt. The increased migration of CerK overexpressing cells was mitigated by the CerK inhibitor NVP-231, by inhibition of the phosphoinositide 3-kinase (PI3K)/Akt pathway and the Rho kinase, but not by inhibition of the classical extracellular signal-regulated kinase (ERK) pathway. Altogether, our data demonstrate for the first time that CerK promotes migration and invasion of metastatic breast cancer cells and that targeting of CerK has potential to counteract metastasis in breast cancer.

Item Type:

Journal Article (Original Article)

Division/Institute:

04 Faculty of Medicine > Pre-clinic Human Medicine > Institute of Pharmacology

Graduate School:

Graduate School for Cellular and Biomedical Sciences (GCB)

UniBE Contributor:

Erhardt, Martin; Zangemeister-Wittke, Uwe and Huwiler, Andrea

Subjects:

600 Technology > 610 Medicine & health

ISSN:

1661-6596

Publisher:

Molecular Diversity Preservation International MDPI

Funders:

[42] Schweizerischer Nationalfonds

Language:

English

Submitter:

Sabrina Cookman

Date Deposited:

25 Mar 2020 12:05

Last Modified:

25 Mar 2020 12:05

Publisher DOI:

10.3390/ijms21041396

PubMed ID:

32092937

Uncontrolled Keywords:

ceramide kinase metastatic breast cancer cells migration and invasion

BORIS DOI:

10.7892/boris.141735

URI:

https://boris.unibe.ch/id/eprint/141735

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