17β-estradiol induces stearoyl-CoA desaturase-1 expression in estrogen receptor-positive breast cancer cells.
17β-estradiol induces stearoyl-CoA desaturase-1 expression in estrogen receptor-positive breast cancer cells.
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DOI：
10.1186/s12885-015-1452-1
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发表时间：
2015-05-29
期刊：
影响因子：
3.8
通讯作者：
Surette ME
中科院分区：
文献类型：
--
作者：
Belkaid A;Duguay SR;Ouellette RJ;Surette ME
为了维持细胞生长，癌细胞表现出以增加的脂肪生成为特征的改变的代谢。硬脂酰辅酶A去饱和酶-1（SCD-1）催化膜生物合成所必需的单不饱和脂肪酸的产生，并且是许多癌细胞类型中细胞增殖所必需的。虽然雌激素是许多雌激素敏感的乳腺癌细胞增殖所必需的，但它也是肝脏和脂肪中SCD-1表达的抑制剂。目前的研究通过研究雌激素对雌激素受体α阳性乳腺癌细胞系中SCD-1表达的影响来解决这一明显的矛盾。将MCF-7和T47 D乳腺癌细胞和永生化MCF-10A乳腺上皮细胞饥饿，然后用17β-雌二醇处理或不处理。通过测量细胞单不饱和/饱和脂肪酸（MUFA/SFA）比率来评估SCD-1活性，并且通过qPCR、免疫印迹和免疫荧光分析来测量SCD-1表达。在用SCD-1抑制剂A959372处理后和在使用siRNA沉默SCD-1后测量SCD-1在细胞增殖中的作用。使用IGF-1 R拮抗剂AG 1024测量IGF-1 R对SCD-1表达的参与。通过qPCR和免疫印迹分析测量SREBP-1c（一种调节SCD-1的转录因子）的表达。17β-雌二醇对MCF-7和T47 D细胞的增殖和SCD-1活性有显著的促进作用，但对MCF-10A细胞无明显影响。因此，与未处理的细胞相比，17β-雌二醇显著增加了MCF-7和T47 D细胞中SCD-1 mRNA和蛋白的表达。用4-OH tamoxifen或siRNA沉默雌激素受体-α处理MCF-7细胞，在很大程度上阻止了17β-雌二醇诱导的SCD-1表达。17β-雌二醇增加SREBP-1c的表达，并诱导SREBP-1的成熟活性60 kDa形式。选择性SCD-1抑制剂或SCD-1的siRNA沉默阻断了17β-雌二醇诱导的细胞增殖和细胞MUFA/SFA比率的增加。IGF-1也诱导SCD-1表达，但程度低于17β-雌二醇。IGF-1 R拮抗剂部分阻断17β-雌二醇诱导的细胞增殖和SCD-1表达，表明17β-雌二醇对SCD-1表达的影响部分通过IGF-1 R信号转导介导。这项研究首次表明，与肝脏和脂肪组织相反，雌激素诱导乳腺癌细胞中SCD-1的表达和活性。这些结果支持SCD-1作为雌激素敏感性乳腺癌的治疗靶点。
To sustain cell growth, cancer cells exhibit an altered metabolism characterized by increased lipogenesis. Stearoyl-CoA desaturase-1 (SCD-1) catalyzes the production of monounsaturated fatty acids that are essential for membrane biogenesis, and is required for cell proliferation in many cancer cell types. Although estrogen is required for the proliferation of many estrogen-sensitive breast carcinoma cells, it is also a repressor of SCD-1 expression in liver and adipose. The current study addresses this apparent paradox by investigating the impact of estrogen on SCD-1 expression in estrogen receptor-α-positive breast carcinoma cell lines. MCF-7 and T47D mammary carcinomas cells and immortalized MCF-10A mammary epithelial cells were hormone-starved then treated or not with 17β-estradiol. SCD-1 activity was assessed by measuring cellular monounsaturated/saturated fatty acid (MUFA/SFA) ratios, and SCD-1 expression was measured by qPCR, immunoblot, and immunofluorescence analyses. The role of SCD-1 in cell proliferation was measured following treatment with the SCD-1 inhibitor A959372 and following SCD-1 silencing using siRNA. The involvement of IGF-1R on SCD-1 expression was measured using the IGF-1R antagonist AG1024. The expression of SREBP-1c, a transcription factor that regulates SCD-1, was measured by qPCR, and by immunoblot analyses. 17β-estradiol significantly induced cell proliferation and SCD-1 activity in MCF-7 and T47D cells but not MCF-10A cells. Accordingly, 17β-estradiol significantly increased SCD-1 mRNA and protein expression in MCF-7 and T47D cells compared to untreated cells. Treatment of MCF-7 cells with 4-OH tamoxifen or siRNA silencing of estrogen receptor-α largely prevented 17β-estradiol-induced SCD-1 expression. 17β-estradiol increased SREBP-1c expression and induced the mature active 60 kDa form of SREBP-1. The selective SCD-1 inhibitor or siRNA silencing of SCD-1 blocked the 17β-estradiol-induced cell proliferation and increase in cellular MUFA/SFA ratios. IGF-1 also induced SCD-1 expression, but to a lesser extent than 17β-estradiol. The IGF-1R antagonist partially blocked 17β-estradiol-induced cell proliferation and SCD-1 expression, suggesting the impact of 17β-estradiol on SCD-1 expression is partially mediated though IGF-1R signaling. This study illustrates for the first time that, in contrast to hepatic and adipose tissue, estrogen induces SCD-1 expression and activity in breast carcinoma cells. These results support SCD-1 as a therapeutic target in estrogen-sensitive breast cancer.
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