近日，國際著名雜志PLoS One在線刊登了廈門大學(xué)藥學(xué)院的研究人員的最新研究成果“Antagonist Effect of Triptolide on AKT Activation by Truncated Retinoid X Receptor-alpha,，”,，文章中,，研究者從傳統(tǒng)中草藥雷公藤分離出活性成分雷公藤甲素（triptolide）,，并在體內(nèi)外實(shí)驗(yàn)中證實(shí)其可以調(diào)控tRXRα介導(dǎo)的癌細(xì)胞存活信號通路。
廈門大學(xué)的曾錦章教授和張曉坤教授為這篇文章的共同通訊作者,。陸娜和劉金星兩位碩士研究生是該文章的共同第一作者,。
從天然產(chǎn)物中尋找抗腫瘤活性成分是發(fā)展抗腫瘤藥物的重要策略之一，雷公藤是我國一種資源比較豐富的傳統(tǒng)中草藥,，其結(jié)構(gòu)多樣的有效成分具有明顯的抗炎,、免疫抑制和抗腫瘤等作用，是開發(fā)治療藥物的一個(gè)寶藏,，但雷公藤具有很大的毒性,，分子靶點(diǎn)和作用機(jī)制不清楚，是迄今制約雷公藤發(fā)展成真正治療藥物的關(guān)鍵,。
在這篇文章中,，研究人員從中藥雷公藤中分離出活性成分雷公藤甲素，并證實(shí)其調(diào)控了tRXRα介導(dǎo)的癌細(xì)胞存活信號通路,。研究結(jié)果顯示雷公藤甲素依賴于細(xì)胞內(nèi)的tRXRα表達(dá)水平強(qiáng)有力地誘導(dǎo)了癌細(xì)胞凋亡,，證實(shí)了tRXRα是雷公藤甲素一個(gè)重要的細(xì)胞內(nèi)靶點(diǎn)。
tRXRα是核受體視黃醇X受體-α（RXRα）的一種在其N-端截短的突變體,，普遍存在于各種腫瘤組織中,，與其全長RXRα?主要定位于細(xì)胞核不同，tRXRα?通常轉(zhuǎn)位于細(xì)胞質(zhì),，通過與p85相互作用激活PI3K/AKT信號轉(zhuǎn)導(dǎo)通路,，是腫瘤微環(huán)境中大量表達(dá)的腫瘤壞死因子TNFα?所依賴的生存通道，tRXRα的高度表達(dá)對于腫瘤的生長有重要的促進(jìn)作用,。
研究人員證實(shí)雷公藤甲素選擇性地誘導(dǎo)了tRXRα降解,，并抑制了tRXRα依賴的AKT活性，但卻沒有影響全長的RXRα,。研究人員還證實(shí)雷公藤甲素靶向tRXRα強(qiáng)有力地激活了TNFα死亡信號,，并促進(jìn)了其他化療的抗癌活性。
新研究確定了雷公藤甲素是tRXRα依賴的存活信號通路的一個(gè)新的調(diào)控物質(zhì),，從而提供了關(guān)于雷公藤甲素作用誘導(dǎo)癌細(xì)胞凋亡機(jī)制的新見解,。雷公藤甲素代表了具有不良副效應(yīng)的傳統(tǒng)中草藥天然產(chǎn)物最有希望的一個(gè)治療先導(dǎo)物。新研究發(fā)現(xiàn)為開發(fā)出用于癌癥治療的改良雷公藤甲素類似物提供了分子基礎(chǔ)和新方向,。（生物谷Bioon.com）
doi:10.1371/journal.pone.0035722
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Antagonist Effect of Triptolide on AKT Activation by Truncated Retinoid X Receptor-alpha
Na Lu1#, Jinxing Liu1#, Jie Liu1, Chunyun Zhang1, Fuquan Jiang1, Hua Wu1, Liqun Chen1, Wenjun Zeng1, Xihua Cao2, Tingdong Yan1, Guanghui Wang1, Hu Zhou2, Bingzhen Lin2, Xiaomei Yan3, Xiao-kun Zhang1,2*, Jin-Zhang Zeng1*
Background Retinoid X receptor-alpha (RXRα) is a key member of the nuclear receptor superfamily. We recently demonstrated that proteolytic cleavage of RXRα resulted in production of a truncated product, tRXRα, which promotes cancer cell survival by activating phosphatidylinositol-3-OH kinase (PI3K)/AKT pathway. However, how the tRXRα-mediated signaling pathway in cancer cells is regulated remains elusive. Methodology/Principal Findings We screened a natural product library for tRXRα targeting leads and identified that triptolide, an active component isolated from traditional Chinese herb Trypterygium wilfordii Hook F, could modulate tRXRα-mediated cancer cell survival pathway in vitro and in animals. Our results reveal that triptolide strongly induces cancer cell apoptosis dependent on intracellular tRXRα expression levels, demonstrating that tRXRα serves as an important intracellular target of triptolide. We show that triptolide selectively induces tRXRα degradation and inhibits tRXRα-dependent AKT activity without affecting the full-length RXRα. Interestingly, such effects of triptolide are due to its activation of p38. Although triptolide also activates Erk1/2 and MAPK pathways, the effects of triptolide on tRXRα degradation and AKT activity are only reversed by p38 siRNA and p38 inhibitor. In addition, the p38 inhibitor potently inhibits tRXRα interaction with p85α leading to AKT inactivation. Our results demonstrate an interesting novel signaling interplay between p38 and AKT through tRXRα mediation. We finally show that targeting tRXRα by triptolide strongly activates TNFα death signaling and enhances the anticancer activity of other chemotherapies Conclusions/Significance Our results identify triptolide as a new xenobiotic regulator of the tRXRα-dependent survival pathway and provide new insight into the mechanism by which triptolide acts to induce apoptosis of cancer cells. Triptolide represents one of the most promising therapeutic leads of natural products of traditional Chinese medicine with unfortunate side-effects. Our findings will offer new strategies to develop improved triptolide analogs for cancer therapy.
