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Abstract
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.
Highlights
Metastatic breast cancer is a devastating disease with a poor prognosis [1,2]
We show a clear correlation between ceramide kinase (CerK) expression, activity, and metastatic potential of the cells, and we demonstrate that CerK substantially contributes to breast cancer migration and invasion by activation of the phosphoinositide 3-kinase (PI3K)/Akt and the Rho kinase pathways
ceramide 1-phosphate (C1P) contributes to cancer cell proliferation and migration, but the underlying mechanism is still unclear
Summary
Metastatic breast cancer is a devastating disease with a poor prognosis [1,2]. There is growing evidence that bioactive lipid molecules are implicated in malignant progression by regulating proliferative, migratory, and invasive behavior of cancer cells. The detailed cellular mechanisms of action and the direct targets of C1P are still largely unclear, targeting of CerK by either genetic approaches, such as siRNA and genetic knockout in mice, or pharmacologically with, e.g., catalytic inhibitors, has unveiled a number of physiological and pathophysiological functions [9] These include regulation of intracellular vesicle formation, fusion and release [10,11,12], as well as cell proliferation and migration [8,13,14], and inflammation [9,15]. CerK has been suggested to increase malignancy, as it was shown that, in pancreatic cancer cells, extracellular C1P, and overexpression of CerK and intracellularly generated C1P, increased migration and invasion This process was dependent on phosphoinositide 3-kinase (PI3K), mTOR, Akt, and RhoA [13]. We show a clear correlation between CerK expression, activity, and metastatic potential of the cells, and we demonstrate that CerK substantially contributes to breast cancer migration and invasion by activation of the PI3K/Akt and the Rho kinase pathways
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