Ceramide Kinase (CERK) Emerges as a Common Therapeutic Target for Triple Positive and Triple Negative Breast Cancer Cells

SIMPLE SUMMARY: Existing chemotherapy treatments for breast cancer patients are high on toxicity. There are very limited options available for triple-positive breast cancer (TPBC) patients, and there have not been any major breakthrough for targeted therapy for triple-negative breast cancer (TNBC) patients. Therefore, there is a need to identify common therapeutic targets for breast cancer patients. In this manuscript, we compared the sphingolipid profiles of cancer cell lines representing TPBC and TNBC, and correlated these profiles with the proliferation and migration properties the of cell types. We then associated the sphingolipid profiles for each subtype specific cell line with transcriptional and translational expression of corresponding metabolizing enzymes. Our results suggested that ceramide kinase (CERK) that catalyzes the synthesis of ceramide-1-phosphates from ceramides is dysregulated in both cell types. We also showed that the targeting of CERK at transcriptional level by siRNA therapeutics or inhibiting the CERK activity by hydrogel-mediated delivery of chemical inhibitors can be an effective strategy to slow down the tumor progression. Therefore, CERK emerges as a potential therapeutic target that can be explored further for cancer therapy. ABSTRACT: Sphingolipids are key signaling biomolecules that play a distinct role in cell proliferation, migration, invasion, drug resistance, metastasis, and apoptosis. Triple-negative (ER−PR−HER2−) and triple-positive (ER+PR+HER2+) breast cancer (called TNBC and TPBC, respectively) subtypes reveal distinct phenotypic characteristics and responses to therapy. Here, we present the sphingolipid profiles of BT-474 and MDA-MB-231 breast cancer cell lines representing the TPBC and TNBC subtypes. We correlated the level of different classes of sphingolipids and the expression of their corresponding metabolizing enzymes with the cell proliferation and cell migration properties of BT-474 and MDA-MB-231 cells. Our results showed that each cell type exhibits a unique sphingolipid profile, and common enzymes such as ceramide kinase (CERK, responsible for the synthesis of ceramide-1-phosphates) are deregulated in these cell types. We showed that siRNA/small molecule-mediated inhibition of CERK can alleviate cell proliferation in BT-474 and MDA-MB-231 cells, and cell migration in MDA-MB-231 cells. We further demonstrated that nanoparticle-mediated delivery of CERK siRNA and hydrogel-mediated sustained delivery of CERK inhibitor to the tumor site can inhibit tumor progression in BT-474 and MDA-MB-231 tumor models. In summary, distinct sphingolipid profiles of TPBC and TNBC representing cell lines provide potential therapeutic targets such as CERK, and nanoparticle/hydrogel mediated pharmacological manipulations of such targets can be explored for future cancer therapeutics.