Department of Molecular Pneumology, University Hospital, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany.
Institute of Nutritional Science, University of Potsdam, Nuthetal, Germany.
Cancer Res. 2017 Nov 1;77(21):5963-5976. doi: 10.1158/0008-5472.CAN-16-3313. Epub 2017 Sep 7.
The lipid hydrolase enzyme acid sphingomyelinase (ASM) is required for the conversion of the lipid cell membrane component sphingomyelin into ceramide. In cancer cells, ASM-mediated ceramide production is important for apoptosis, cell proliferation, and immune modulation, highlighting ASM as a potential multimodal therapeutic target. In this study, we demonstrate elevated ASM activity in the lung tumor environment and blood serum of patients with non-small cell lung cancer (NSCLC). RNAi-mediated attenuation of in human NSCLC cells rendered them resistant to serum starvation-induced apoptosis. In a murine model of lung adenocarcinoma, ASM deficiency reduced tumor development in a manner associated with significant enhancement of Th1-mediated and cytotoxic T-cell-mediated antitumor immunity. Our findings indicate that targeting ASM in NSCLC can act by tumor cell-intrinsic and -extrinsic mechanisms to suppress tumor cell growth, most notably by enabling an effective antitumor immune response by the host. .
脂质水解酶酸性鞘磷脂酶（ASM）是将细胞膜成分神经鞘磷脂转化为神经酰胺所必需的。在癌细胞中，ASM 介导的神经酰胺产生对于细胞凋亡、细胞增殖和免疫调节很重要，这凸显了 ASM 作为一种潜在的多模态治疗靶点的重要性。在这项研究中，我们证明了肺癌肿瘤环境和非小细胞肺癌（NSCLC）患者血清中的 ASM 活性升高。在人类 NSCLC 细胞中，RNAi 介导的降低了 ASM 的活性，使其对血清饥饿诱导的细胞凋亡产生抗性。在肺腺癌的小鼠模型中，ASM 缺乏以与显著增强 Th1 介导和细胞毒性 T 细胞介导的抗肿瘤免疫相关的方式降低肿瘤的发展。我们的研究结果表明，在 NSCLC 中靶向 ASM 可以通过肿瘤细胞内在和外在的机制来抑制肿瘤细胞的生长，最显著的是通过宿主产生有效的抗肿瘤免疫反应。
