VDR independent induction of acid-sphingomyelinase by 1,23(OH)2 D3 in gastric cancer cells: Impact on apoptosis and cell morphology
VDR independent induction of acid-sphingomyelinase by 1,23(OH)2 D3 in gastric cancer cells: Impact on apoptosis and cell morphology
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DOI：
10.1016/j.biochi.2017.11.011
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发表时间：
2018-03-01
期刊：
影响因子：
3.9
通讯作者：
Codini, Michela
中科院分区：
文献类型：
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作者：
Albi, Elisabetta;Cataldi, Samuela;Codini, Michela
已知1 α， 25-二羟基维生素D-3 (1,23（OH)(2) D-3）在癌症中发挥双重作用，通过1,23(OH)(2) D-3受体（VDR）和10号染色体上缺失的磷酸酶和紧张素同源物（PTEN）促进或抑制癌变。VDR的Fok I多态性可能通过自调节间接影响受体水平。中性鞘磷脂酶参与非经典vdr介导的基因组通路对1,23(OH)(2) D-3治疗的反应。NCI-N87人胃癌细胞中VDR的Fok I多态性及酸性鞘磷脂酶与1,23(OH)(2) D-3的关系尚未见报道。在这里，我们发现NCI-N87人胃癌细胞是Fok I ‘C’等位基因的纯合子；导致VDR的三个氨基酸截断的蛋白质形式。令人惊讶的是，1,23(OH)(2) D-3处理强烈下调了VDR的表达，而酸性鞘磷脂酶和PTEN的表达上调。1,23(OH)(2) D-3处理后，中性鞘磷脂酶表达无变化，而酸性鞘磷脂酶活性增加。此外，1,23(OH)(2) D-3诱导caspase 8、CDKN2B、MAP3K5、细胞色素C凋亡基因的过表达。形态学分析显示，一些非常大的圆形或椭圆形细胞和小细胞呈角状或梭状延伸，经mb -1免疫检测和Hercep试验证实。综上所述，我们的结果表明，1,23(OH)(2) D-3在胃癌细胞中的作用不依赖于1,23(OH)(2) D-3受体，并提示酸性鞘磷脂酶可能是诱导分子事件的靶点。(c) 2017年Elsevier B.V.出版
1 alpha, 25-dihydroxyvitamin D-3 (1,23(OH)(2) D-3) is known to play a dual role in cancer, by promoting or inhibiting carcinogenesis via 1,23(OH)(2) D-3 receptor (VDR) and phosphatase and tensin homolog deleted on chromosome 10 (PTEN). Fok I polymorphism of VDR may indirectly influence the receptor levels through autoregulation. The involvement of neutral sphingomyelinase in the non-classic VDR-mediated genomic pathway response to 1,23(OH)(2) D-3 treatment has been reported. Until now no information were reported about Fok I polymorphism of VDR in NCI-N87 human gastric cancer cells and the relation between acid sphingomyelinase and 1,23(OH)(2) D-3. Herein, we showed that NCI-N87 human gastric cancer cells are homozygous for the Fok I 'C' allele; resulting in a three amino acid-truncated protein form of the VDR. Surprisingly 1,23(OH)(2) D-3 treatments strongly down-regulated the expression of VDR whereas acid sphingomyelinase and PTEN expression were upregulated. No changes of neutral sphingomyelinase expression were observed after 1,23(OH)(2) D-3 treatment, whereas acid sphingomyelinase activity increased. Furthermore 1,23(OH)(2) D-3 induced over-expression of caspase 8, CDKN2B, MAP3K5, cytochrome C apoptotic genes. Morphological analysis highlighted some very large round or oval cells and small cells with angular or fusiform extensions, confirmed by MIB-1 immunodetection and Hercep test.Taken together our results indicated that the action of 1,23(OH)(2) D-3 in gastric cancer cells was independent on 1,23(OH)(2) D-3 receptor and suggested the acid sphingomyelinase as a possible target to induce molecular events. (c) 2017 Published by Elsevier B.V.