Runx regulation of sphingolipid metabolism and survival signaling.
Runx regulation of sphingolipid metabolism and survival signaling.
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DOI：
10.1158/0008-5472.can-10-0726
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发表时间：
2010-07-15
期刊：
影响因子：
11.2
通讯作者：
Neil JC
中科院分区：
文献类型：
--
作者：
Kilbey A;Terry A;Jenkins A;Borland G;Zhang Q;Wakelam MJ;Cameron ER;Neil JC
Runx 基因（Runx1、2 和 3）调节发育过程中的细胞命运，并且可以作为癌症中的癌基因或肿瘤抑制基因发挥作用。异位 Runx 表达的致癌潜力已在转基因小鼠中得到证实，这些转基因小鼠与过度表达的 Myc 产生有效的协同作用，形成淋巴瘤，并且在已建立的成纤维细胞中，其形态发生改变，致瘤性增加。过度表达的 Runx 基因的候选致癌功能包括响应内在和外在应激而抵抗细胞凋亡。在寻找负责 Runx 表型这一方面的基因靶标时，我们确定了鞘脂代谢中的三种关键酶（Sgpp1、Ugcg 和 St3gal5/Siat9）作为 Runx 转录调节的直接靶标，其方式与生存和凋亡抵抗一致。与基因表达的这些变化一致，质谱分析表明，异位 Runx 减少了 NIH3T3 成纤维细胞中的细胞内长链神经酰胺，并升高了细胞外 1 磷酸鞘氨醇 (S1P)。 Runx 表达还对抗 JNK 和 p38MAPK（神经酰胺诱导死亡的关键介质）的激活，并抑制响应外源 TNFα 的细胞凋亡的发生。异位 Runx 赋予的生存优势可以通过外源 S1P 部分重现，并且伴随着 p38MAPK 磷酸化的减少。这些结果揭示了转录因子癌基因和涉及癌细胞存活和化疗耐药性的脂质信号通路之间的新联系。
The Runx genes (Runx1, 2 and 3) regulate cell fate in development and can operate as either oncogenes or tumour suppressors in cancer. The oncogenic potential of ectopic Runx expression has been demonstrated in transgenic mice that develop lymphoma in potent synergy with over-expressed Myc, and in established fibroblasts that display altered morphology and increased tumorigenicity. Candidate oncogenic functions of over-expressed Runx genes include resistance to apoptosis in response to intrinsic and extrinsic stresses. In a search for gene targets responsible for this aspect of Runx phenotype we have identified three key enzymes in sphingolipid metabolism (Sgpp1, Ugcg and St3gal5/Siat9) as direct targets for Runx transcriptional regulation, in a manner consistent with survival and apoptosis resistance. Consistent with these changes in gene expression, mass spectrometric analysis demonstrated that ectopic Runx reduces intracellular long chain ceramides in NIH3T3 fibroblasts and elevated extracellular sphingosine 1 phosphate (S1P). Runx expression also opposed activation of JNK and p38MAPK, key mediators of ceramide-induced death, and suppressed the onset of apoptosis in response to exogenous TNFα. The survival advantage conferred by ectopic Runx could be partially recapitulated by exogenous S1P and was accompanied by reduced phosphorylation of p38MAPK. These results reveal a novel link between transcription factor oncogenes and lipid signalling pathways involved in cancer cell survival and chemoresistance.