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

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.

Ceramide kinase mediates intrinsic resistance and inferior response to chemotherapy in triple‐negative breast cancer by upregulating Ras/ERK and PI3K/Akt pathways

“…Apart from chemoresistance, we showed that CERK promoted TNBC migration (Fig. 2 d, e), which is in line with the findings of a recent study on the contribution of CERK to migration and invasion in metastatic breast cancer cells [ 13 ]. Similar to CERK, C1P was reported to increase migration and invasion in pancreatic cancer cells [ 8 ].…”

“…It is interesting to note that the upregulation of CERK expression (tumor/normal > 2) is found only in some TNBC patients, with a significant association with chemoresistance (Table 1 ). Previous studies using cell models and publicly available microarray data show that elevated CERK expression is linked with metastatic breast cancer and increased risk of recurrence in patients with breast cancer [ 12 , 13 , 23 ]. Specifically, CERK overexpression is also associated with decreased recurrence-free survival in patients with ER-negative breast cancer [ 14 ].…”

“…CERK was shown to be upregulated following HER2/neu pathway inhibition in breast cancer cells [ 12 ]. In metastatic breast cancer cells, PI3K, Akt, mTOR, and RhoA were demonstrated to be responsible for migration regulation by CERK [ 13 ]. Using both knockdown and overexpression approaches, our study demonstrated that, in addition to PI3K/Akt/mTOR and Rho pathways, CERK activates the Ras/ERK pathway in TNBC cells (Fig.…”

“…CERK promotes tumor cell survival and mammary tumor recurrence [ 12 ]. It is upregulated in metastatic breast cancer cells and contributes to migration and invasion by activating PI3K and Akt [ 13 ]. High CERK expression is associated with poorer prognosis in ER-negative breast cancer [ 14 ].…”

Lipidomics Identified Lyso-phosphatidylcholine and Phosphatidylethanolamine as Novel Biomarkers for Diagnosis of Laryngeal Cancer

“…The imbalance in ceramide will greatly affect the physicochemical properties of cell, leading to cellular dysfunction. It has been demonstrated that ceramide metabolism is altered in numerous cancers characterized by an elevation of the Cer pro le in tumor tissue and cancer cells [7,12,13]. We speculated that the signi cant increase in the level of the Cer lipid class in LaC could have resulted from the elevated expression of the enzymes responsible for the synthesis of ceramide.…”