第二型內皮素與第一型類胰島素生長因子對3T3-L1前脂肪細胞生長刺激作用的信息傳導路徑;Signal transduction pathway of endothelin-2 with IGF-I in the growth stimulation of 3T3-L1 preadipocytes

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题名:	第二型內皮素與第一型類胰島素生長因子對3T3-L1前脂肪細胞生長刺激作用的信息傳導路徑;Signal transduction pathway of endothelin-2 with IGF-I in the growth stimulation of 3T3-L1 preadipocytes
作者:	鄒宇涵;Tsou, Yu-Han
贡献者:	生命科學系
关键词:	第二型內皮素;第一型類胰島素生長因子;前脂肪細胞;endothelin-2;IGF-I;preadipocyte
日期:	2021-01-21
上传时间:	2021-03-18 16:50:38 (UTC+8)
出版者:	國立中央大學
摘要:	內皮素（ETs）是一種21個氨基酸的?激素，從豬主動脈內皮細胞培養上清液中分離出來，被稱為有效的血管收縮劑和加壓劑。儘管有文獻指出ETs增強第一型類胰島素生長因子（IGF-I）對前列腺癌細胞生長的刺激作用，但尚未發現ET-2是否與IGF-I有相互作用在脂肪細胞的報導。使用3T3-L1前脂肪細胞，我們發現單獨的ET-2對細胞生長沒有影響，如在細胞數量，細胞存活和BrdU incorporation的變化所表明。在存在IGF-1的情況下，ET-2增強了IGF-1誘導的細胞數量和細胞增殖的增加。當檢驗ET-2信號通路時，透過內皮素受體的特異性抑製劑ETAR拮抗劑（BQ610）而不是ETBR拮抗劑（BQ788）的預處理阻止了ET-2對IGF-I誘導的細胞數量和細胞存活增加的增強作用。進一步的在Western blot中表明，ET-2、IGF-I及其組合傾向於時間依賴性的刺激AKT、ERK和STAT3蛋白的磷酸化。有趣的是，與單獨的IGF-I相比，ET-2在一小時增強了IGF-I刺激的STAT3磷酸化蛋白，但未增強AKT或ERK1/2。但是，在15和30分鐘時預處理ET-2可以增強IGF-I刺激的AKT和ERK蛋白的磷酸化。此外，預處理STAT3抑制劑（AG490）、ERK1/2抑制劑（U0126）和PI3K/AKT抑制劑（Wortmannin）阻止了ET-2和IGF-I對細胞數和細胞存活的刺激，同時也分別降低各自pSTAT3，pAKT和pERK蛋白水平。總之，STAT3以及較小程度的AKT和ERK蛋白對於ET-2和IGF-I以ETAR依賴性而不是ETBR依賴性的方式對前脂肪細胞的生長產生協同作用是必需的。;Endothelins (ETs) are a 21 amino acid (aa) peptide hormone that was known as a potent vasoconstrictor and pressor substance isolated from the culture supernatant of porcine aortic endothelial cells. Although the ETs have been also reported to potentiate the stimulatory effect of insulin-like growth factor (IGF)-I on the growth of prostate cancer cells, no reports are found whether ET-2 interacts with IGF-I in fat cells. Using 3T3-L1 preadipocytes, we found that ET-2 alone had no effect on cell growth, as indicated by changes in levels of cell number, BrdU incorporation, and cell viability. In the presence of IGF-I, ET-2 enhanced IGF-I-induced increases in both cell number and cell proliferation. When the ET-2 signaling pathway was examined, pretreatment with the specific inhibitors of endothelin receptors, ETAR antagonist (BQ610) but not ETBR antagonist (BQ788), prevented the enhancing effect of ET-2 on IGF-I-induced increases in both cell number and cell viability. Further Western blotting analysis showed that ET-2, IGF-I, and their combination tended to time-dependently stimulate phosphorylations of AKT, ERK, and STAT3 proteins. Interestingly, ET-2 at 1 h enhanced IGF-I-stimulated phosphorylation of STAT3, but not AKT or ERK1/2, proteins when compared to IGF-I alone. But, pretreatment with ET-2 at 15 and 30 min enhanced IGF-I-stimulated phosphorylation of AKT and ERK proteins. Moreover, pre-treatment with STAT3 inhibitor (AG490), ERK1/2 inhibitor (U0126), and PI3K/AKT inhibitor (wortmannin) prevented the stimulation of ET-2 and IGF-I in cell number and cell viability, respectively, as well as reducing the level of respective pSTAT3, pAKT, and pERK proteins. In conclusions, STAT3 and, to a lesser extent of AKT and ERK proteins are necessary for the synergistic effect of ET-2 and IGF-I on the growth of preadipocytes in an ETAR-dependent and ETBR-independent manner.
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