來自美國國家健康研究院（NIH）科學(xué)家在小鼠實(shí)驗(yàn)中,，成功發(fā)現(xiàn)了一種能有效抑制人的乳腺癌細(xì)胞生長的小分子RGS16,，該發(fā)現(xiàn)對開發(fā)治療乳腺癌的新方法和藥物具有重要作用。相關(guān)研究成果發(fā)表在美國《生物化學(xué)雜志》上,。
乳腺癌是一種女性常見的惡性腫瘤,。20世紀(jì)90年代以來,，乳腺癌的發(fā)病率在世界各地均有上升趨勢,，歐洲和北美有超過10%的婦女患有這種腫瘤,。目前,，治療乳腺癌的主要方法是手術(shù)切除,、放射和化學(xué)治療。但是,，對于已經(jīng)轉(zhuǎn)移了的乳腺癌病人,，手術(shù)治療不能根除。此外,，放射和化學(xué)治療對人體有很大的損傷和副作用,。
長期以來，科學(xué)家們一直致力于研究新的乳腺癌治療方法,，例如基因或小分子療法,，這種治療方法的突出優(yōu)點(diǎn)是在晚期癌癥的治療中沒有或只有輕微的副作用。
科學(xué)家的最新研究是利用病毒載體和轉(zhuǎn)染技術(shù)把RGS16基因或者干擾RNA(siRNA) 導(dǎo)入人的癌細(xì)胞中,，使RGS16蛋白的表達(dá)增強(qiáng)或抑制,。然后，應(yīng)用細(xì)胞熒光標(biāo)記和細(xì)胞活力分析等手段,，測定細(xì)胞的繁殖和增長速度,。研究人員還通過免疫沉淀和免疫化學(xué)反應(yīng),，探索RGS16所作用的生物信息鏈。
研究表明,，RGS16是通過一種細(xì)胞生長因子（EGF）的信息鏈來調(diào)控乳腺癌細(xì)胞生長的,。當(dāng)EGF和它的細(xì)胞表面受體（EGFR）結(jié)合時，可導(dǎo)致一些蛋白激酶（例如Akt）的磷酸化,。這些磷酸化激酶一方面促進(jìn)癌細(xì)胞繁殖和生長,，另一方面可以抑制癌細(xì)胞的凋亡，從而導(dǎo)致腫瘤形成,。RGS16通過結(jié)合在EGFR復(fù)合體上,，使得蛋白激酶的磷酸化被抑制，從而延緩了癌細(xì)胞生長,。
大量試驗(yàn)證明,，當(dāng)RGS16基因表達(dá)加強(qiáng)時，乳腺癌細(xì)胞的生長得到延緩,，并最后死亡,。相反，如果RGS16基因表達(dá)被抑制,，這種癌細(xì)胞會加快生長,。這些成果表明，小分子RGS16很有可能成為治療乳腺癌的新方法,，對新的乳腺癌藥物開發(fā)具有重要意義,。對于開發(fā)用于人體的癌癥治療方法來說，RGS16應(yīng)是安全和副作用小的選擇,。
目前研究人員正在應(yīng)用小鼠做進(jìn)一步研究,。他們將人的乳腺癌細(xì)胞移植到小鼠體內(nèi)，然后測定RGS16在腫瘤形成和生長上的作用,，進(jìn)一步探索RGS16調(diào)控腫瘤生長的分子機(jī)理,。(生物谷Bioon.com)
生物谷推薦英文摘要：
JBC doi: 10.1074/jbc.M109.028407
RGS16 Inhibits Breast Cancer Cell Growth by Mitigating Phosphatidylinositol 3-Kinase Signaling*
Genqing Liang, Geetanjali Bansal1, Zhihui Xie and Kirk M. Druey2
Aberrant activity of the phosphatidylinositol 3-kinase (PI3K) pathway supports growth of many tumors including those of breast, lung, and prostate. Resistance of breast cancer cells to targeted chemotherapies including tyrosine kinase inhibitors (TKI) has been linked to persistent PI3K activity, which may in part be due to increased membrane expression of epidermal growth factor (EGF) receptors (HER2 and HER3). Recently we found that proteins of the RGS (regulator of G protein signaling) family suppress PI3K activity downstream of the receptor by sequestering its p85α subunit from signaling complexes. Because a substantial percentage of breast tumors have RGS16 mutations and reduced RGS16 protein expression, we investigated the link between regulation of PI3K activity by RGS16 and breast cancer cell growth. RGS16 overexpression in MCF7 breast cancer cells inhibited EGF-induced proliferation and Akt phosphorylation, whereas shRNA-mediated extinction of RGS16 augmented cell growth and resistance to TKI treatment. Exposure to TKI also reduced RGS16 expression in MCF7 and BT474 cell lines. RGS16 bound the amino-terminal SH2 and inter-SH2 domains of p85α and inhibited its interaction with the EGF receptor-associated adapter protein Gab1. These results suggest that the loss of RGS16 in some breast tumors enhances PI3K signaling elicited by growth factors and thereby promotes proliferation and TKI evasion downstream of HER activation.
