鞘脂是在细胞增殖中起独特作用的关键信号生物分子,迁移,入侵,耐药性,转移,和凋亡。三阴性(ER-PR-HER2-)和三阳性(ER+PR+HER2+)乳腺癌(称为TNBC和TPBC,分别)亚型揭示了不同的表型特征和对治疗的反应。这里,我们介绍了代表TPBC和TNBC亚型的BT-474和MDA-MB-231乳腺癌细胞系的鞘脂谱。我们将不同类别的鞘脂的水平及其相应代谢酶的表达与BT-474和MDA-MB-231细胞的细胞增殖和细胞迁移特性相关联。我们的结果表明,每种细胞类型都表现出独特的鞘脂特征,和常见的酶,如神经酰胺激酶(CERK,负责神经酰胺-1-磷酸的合成)在这些细胞类型中失调。我们表明siRNA/小分子介导的CERK抑制可以减轻BT-474和MDA-MB-231细胞的增殖,和MDA-MB-231细胞中的细胞迁移。我们进一步证明了纳米颗粒介导的CERKsiRNA递送和水凝胶介导的CERK抑制剂向肿瘤部位的持续递送可以抑制BT-474和MDA-MB-231肿瘤模型中的肿瘤进展。总之,代表细胞系的TPBC和TNBC的不同鞘脂谱提供了潜在的治疗靶标,例如CERK,和纳米颗粒/水凝胶介导的此类靶标的药理学操作可以被探索用于未来的癌症治疗。
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.