文章：

半乳糖神经酰胺上调BCL2基因表达并下调TNFRSF1B与TNFRSF9基因表达，在乳腺癌细胞中发挥抗凋亡分子作用

Galactosylceramide Upregulates the Expression of theBCL2Gene and Downregulates the Expression ofTNFRSF1BandTNFRSF9Genes, Acting as an Anti-Apoptotic Molecule in Breast Cancer Cells

原文发布日期：17 January 2024

DOI: 10.3390/cancers16020389

类型: Article

开放获取: 是

英文摘要：

Galactosylceramide (GalCer) increases the resistance of breast cancer cells to doxorubicin, paclitaxel, and cisplatin by acting as an anti-apoptotic molecule. GalCer was found to specifically downregulate the levels of the pro-apoptoticTNFRSF1BandTNFRSF9genes and upregulate the levels of the anti-apoptoticBCL2gene, suggesting that this glycosphingolipid regulates their expression at the transcriptional level. Consistent with this hypothesis, MDA-MB-231 and MCF7 breast cancer cells with high levels of GalCer showed lower activity of theTNFRSF1BandTNFRSF9promoters than cells lacking GalCer. In contrast, the activity of theBCL2promoter was higher in MCF7 cells overproducing GalCer than in MCF7 cells without GalCer. However, no difference inBCL2promoter activity was observed between MDA-MB-231 cells with high and no GalCer content. Instead, we found that high levels of GalCer increased the stability of Bcl-2 mRNA. Subsequent studies showed that breast cancer cells with high levels of GalCer are characterized by significantly lower expression of P53. Importantly, inhibition of P53 expression by siRNA in MCF7 and MDA-MB-231 cells lacking GalCer resulted in decreased expression and promoter activity of theTNFRS1BandTNFRSF9genes. On the other hand, increased expression and promoter activity of theBCL2gene was found in such MCF7 cells, and increased stability of Bcl-2 transcripts was observed in such MDA-MB-231 cells. Taken together, these data strongly suggest that the regulatory protein that simultaneously increases the expression of theTNFRSF1BandTNFRSF9genes and decreases the expression of theBCL2gene and the stability of Bcl-2 transcripts is most likely P53, the expression of which is GalCer dependent.

摘要翻译： 

半乳糖神经酰胺（GalCer）通过发挥抗凋亡分子的作用，能够增强乳腺癌细胞对阿霉素、紫杉醇和顺铂的耐药性。研究发现，GalCer能够特异性地下调促凋亡基因TNFRSF1B和TNFRSF9的表达水平，同时上调抗凋亡基因BCL2的表达水平，这表明该鞘糖脂在转录水平上调控了这些基因的表达。与此假说一致，高表达GalCer的MDA-MB-231和MCF7乳腺癌细胞中TNFRSF1B和TNFRSF9启动子的活性低于不表达GalCer的细胞。相反，在过量产生GalCer的MCF7细胞中，BCL2启动子的活性高于不表达GalCer的MCF7细胞。然而，在高表达与不表达GalCer的MDA-MB-231细胞之间，未观察到BCL2启动子活性的差异。相反，我们发现高水平的GalCer能够增加Bcl-2 mRNA的稳定性。后续研究表明，高表达GalCer的乳腺癌细胞具有显著较低的P53表达特征。重要的是，在不表达GalCer的MCF7和MDA-MB-231细胞中，通过siRNA抑制P53表达会导致TNFRSF1B和TNFRSF9基因的表达及启动子活性降低。另一方面，在此类MCF7细胞中观察到BCL2基因的表达及启动子活性增加，而在此类MDA-MB-231细胞中则观察到Bcl-2转录本的稳定性增强。综上所述，这些数据强烈表明，同时增加TNFRSF1B和TNFRSF9基因表达并降低BCL2基因表达及Bcl-2转录本稳定性的调控蛋白很可能是P53，其表达依赖于GalCer。

原文链接：

Galactosylceramide Upregulates the Expression of theBCL2Gene and Downregulates the Expression ofTNFRSF1BandTNFRSF9Genes, Acting as an Anti-Apoptotic Molecule in Breast Cancer Cells