Division of Hepatobiliary and Pancreatic Surgery, Department of Surgery, Kaohsiung Medical University Hospital, Kaohsiung 807, Taiwan.
Department of Surgery, School of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung 807, Taiwan.
Int J Mol Sci. 2019 Sep 2;20(17):4292. doi: 10.3390/ijms20174292.
Ceramide is a sphingolipid which regulates a variety of signaling pathways in eukaryotic cells. Exogenous ceramide has been shown to induce cellular apoptosis. In this study, we observed that exogenous ceramide induced two distinct morphologies of cell fate following C-ceramide treatment between the two breast cancer cell lines MCF-7 (wild type 53) and MDA-MB-231 (mutant 53) cells. The growth assessment showed that C-ceramide caused significant growth inhibition and apoptosis in MDA-MB-231 cells through down-regulating the expression of mutant 53 whereas up-regulating the expression of pro-apoptotic Bad, and the proteolytic activation of caspase-3. However, senescence-associated (SA)-β-galactosidase (β-gal) was regulated in MCF-7 cells after C-ceramide treatment. The results of proliferation and apoptosis assays showed that MCF-7 cells were more resistant to C-ceramide treatment compared to MDA-MB-231 cells. Furthermore, C-ceramide treatment induced a time-responsive increase in Rb protein, a key regulator of senescence accompanied with the upregulation of both mRNA level and protein level of SA-genes PAI-1 and TGaseII in MCF-7 but not in MDA-MB-231 cells, suggesting that some cancer cells escape apoptosis through modulating senescence-like phenotype. The results of our present study depicted the mechanism of C-ceramide-resistant breast cancer cells, which might benefit the strategic development of ceramide-based chemotherapeutics against cancer in the future.
神经酰胺是一种鞘脂，可调节真核细胞中的多种信号通路。外源性神经酰胺已被证明可诱导细胞凋亡。在这项研究中，我们观察到两种不同的乳腺癌细胞系 MCF-7（野生型 53）和 MDA-MB-231（突变型 53）在 C-神经酰胺处理后，外源性神经酰胺诱导了两种不同的细胞命运形态。生长评估表明，C-神经酰胺通过下调突变型 53 的表达，上调促凋亡 Bad 的表达，以及激活 caspase-3 的蛋白水解，导致 MDA-MB-231 细胞的显著生长抑制和凋亡。然而，在 C-神经酰胺处理后，MCF-7 细胞中的衰老相关（SA）-β-半乳糖苷酶（β-gal）受到调节。增殖和凋亡测定的结果表明，与 MDA-MB-231 细胞相比，MCF-7 细胞对 C-神经酰胺处理更具抗性。此外，C-神经酰胺处理诱导 Rb 蛋白的时间反应性增加，Rb 蛋白是衰老的关键调节因子，伴随着 SA-基因 PAI-1 和 TGaseII 的 mRNA 水平和蛋白水平的上调，这在 MCF-7 中而不是在 MDA-MB-231 细胞中，表明一些癌细胞通过调节类似衰老的表型来逃避凋亡。本研究的结果描绘了 C-神经酰胺耐药乳腺癌细胞的机制，这可能有助于未来基于神经酰胺的化疗药物治疗癌症的战略发展。
