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

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.

Unique sphingolipid signature identifies luminal and triple‐negative breast cancer subtypes

“…Increase in ceramide levels also lead to higher levels of glucosylceramides in TNBC tumors, indicative of increased resistance to chemotherapy, a major challenge in TNBC subtype 41 . Tumor of luminal subtype shows pronounced proliferation phenotype, whereas TNBC subtype exhibits distinctly elevated invasion and metastatic phenotype that justifies higher sphingomyelin level in luminal tumors and a higher S1P level in TNBC subtype 42 . Lower sphingomyelin and C1P levels match high ceramide levels in TNBC tissue supporting “sphingodynamic model” that multiple rheostats exist and balance dysregulated sphingolipids during tumor progression.…”

The Critical Impact of Sphingolipid Metabolism in Breast Cancer Progression and Drug Response

“…The different roles played by CerK in more aggressive metastatic BC cell lines with respect to non-metastatic cell lines have been substantiated in a recent and exhaustive study, reporting a detailed analysis of SL profiles and the transcriptional and translational expressions of corresponding metabolizing enzymes in TPBC BT-474 and TNBC MDA-MB-231 cells: each cell type exhibited a unique SL profile, likely responsible for their unique phenotypic behavior, and common enzymes, including CerK, were dysregulated in both cell lines [61]. However, although CerK can be a potential target to contrast tumor cell proliferation and migration in both cell subtypes, siRNA-or NVP-231-mediated CerK inhibition showed that CerK could play different roles in more aggressive metastatic BC cell lines with respect to non-metastatic cell lines.…”

Association between abnormal lipid metabolism and tumor

“…In triple negative breast cancer, the up regulation of CERK is significantly related to its chemoresistance, which may be mediated by the up regulation of Ras/ERK and PI3K/Akt pathways ( 64 ). It is worth noting that CERK has become a common therapeutic target for triple positive and triple negative breast cancer cells ( 65 ). The inhibition of acid ceramidase in CDase family causes mitochondrial dysfunction and oxidative stress in pancreatic cancer cells, thus playing an anti-tumor role ( 66 ).…”

“…In addition, nanoparticle mediated CERK siRNA delivery and hydrogel mediated continuous delivery of CERK inhibitors to tumor sites can also inhibit tumor progression ( 65 ).…”