西安交通大学：人参靶向低氧诱导因子 阻断卵巢癌转移
Ginsenoside 20(S)-Rg3 Targets HIF-1α to Block Hypoxia-Induced Epithelial-Mesenchymal Transition in Ovarian Cancer Cells
卵巢癌是以上皮性卵巢癌(epi卵巢癌，EOC)的形式存在，是妇科最致命的恶性肿瘤。卵巢癌患者的低生存率与其恶性侵袭转移有关。导致卵巢癌细胞侵袭和转移的关键是缺氧的肿瘤微环境, 导致稳定的低氧诱导因子- 1α(HIF-1α)介导肿瘤细胞浸润和转移。
卵巢癌是以上皮性卵巢癌的形式存在，是妇科最致命的恶性肿瘤
卵巢癌患者的预后仍然很差，主要是由于恶性肿瘤进展。由于上皮-间充质转化(epi- mesenchymal transition, EMT)是介导癌细胞侵袭转移的重要机制，靶向EMT过程中更有效、毒性更小的化合物抑制转移对卵巢癌的治疗有很大的治疗价值。
EMT最初是在胚胎发育过程中发现的，后来发现它与肿瘤的侵袭转移过程密切相关。EMT过程中细胞经历一个从极化上皮表型间质表型,一个生物事件的特点是细胞形态学变化从一个鹅卵石形状分散成形状,失去上皮特异性蛋白质收购间叶细胞特异性标记和属性,和增强细胞的能动性和入侵的过渡。
我们首次发现，中药人参的药理活性成分人参皂苷20(S)-Rg3，在体外和体内，能有效阻断低氧诱导的卵巢癌细胞转化（EMT）和转移。
人参皂苷20(S)-Rg3靶向低氧诱导因子，阻断卵巢癌转移
机械的研究证实20(S)-Rg3的作用方式,通过激活ubiquitin-proteasome途径促进HIF-1α退化从而降低低氧诱导因子1α的表达(HIF-1α)。
HIF-1α的减少导致通过上皮细胞特异性标记物E-cadherin Snail的转录抑制的上调，
和在低氧条件下间质细胞特异性标记物vimentin的下调。
重要的是，20(S)-Rg3在卵巢癌裸鼠异种移植模型中有效抑制了上皮-间充质转化（EMT），有望成为一种新的抗癌治疗药物。
Ginsenoside 20(S)-Rg3 Targets HIF-1α to Block Hypoxia-Induced Epithelial-Mesenchymal Transition in Ovarian Cancer Cells
Ting Liu,# 1 Le Zhao,# 1 Yan Zhang, 1 Wei Chen, 2 Dan Liu, 3 Huilian Hou, 4 Lu Ding, 1 and Xu Li 1 , *Joseph Najbauer, Editor1 Center for Translational Medicine, the First Affiliated Hospital School of Medicine, Xi'an Jiaotong University, Xi'an, China,2 Center for Laboratory Medicine, the First Affiliated Hospital School of Medicine, Xi'an Jiaotong University, Xi'an, China,3 Department of Gynaecology and Obstetrics, the First Affiliated Hospital School of Medicine, Xi'an Jiaotong University, Xi'an, China,4 Department of Pathology, the First Affiliated Hospital School of Medicine, Xi'an Jiaotong University, Xi'an, China,
Ovarian cancer, existing predominantly in the form of epithelial ovarian cancer (EOC), is the most lethal gynecologic malignancy [1], [2]. The low survival rate of patients with ovarian cancer is associated with its vicious nature of invasion and metastasis. Among the critical contributors to the invasive and metastatic capability of ovarian cancer cells is hypoxia of the tumor microenvironment [3], [4], which mediates tumor cell invasion and metastasis through stabilization of hypoxia-inducible factor-1 alpha (HIF-1α) [5], [6].
In normoxic cells, HIF-1α is hydroxylated by a family of proline hydroxylases (PHD1-3) at Pro402 and Pro564, leading to a conformational change that promotes HIF-1α binding to the von Hippel Lindau protein (VHL) - a component of the large E3 ubiquitin ligase complex that mediates proteasomal degradation of HIF-1α [7], [8]. Under hypoxic conditions, low oxygen levels preclude proline hydroxylation, which leads to HIF-1α stabilization and subsequent formation of a heterodimer with constitutively expressed HIF-1β. The bioactive HIF-1 dimer regulates, as a transcription factor, the expression of a broad range of genes involved not only in cell cycle, apoptosis [9], angiogenesis [10], [11] and metabolism [12] in response to the hypoxic environment, but also in a cellular process called epithelial-mesenchymal transition (EMT) [13]–[15].
Identified first in embryonic development, EMT has been found later to be closely involved in the process of cancer invasion and metastasis [16], [17]. During the EMT process cells undergo a transition from a polarized epithelial phenotype to a mesenchymal phenotype [18], a biological event characterized by cell morphology change from a cobble-stone shape to a dispersed fibroblastoid shape, loss of epithelial cell-specific protein markers and acquisition of mesenchymal cell-specific properties, and enhanced cell motility and invasion.
The prognosis of patients with ovarian cancer has remained poor mainly because of aggressive cancer progression. Since epithelial-mesenchymal transition (EMT) is an important mechanism mediating invasion and metastasis of cancer cells, targeting the EMT process with more efficacious and less toxic compounds to inhibit metastasis is of great therapeutic value for the treatment of ovarian cancer. We have found for the first time that the ginsenoside 20(S)-Rg3, a pharmacologically active component of the traditional Chinese herb Panax ginseng, potently blocks hypoxia-induced EMT of ovarian cancer cells in vitro and in vivo. Mechanistic studies confirm the mode of action of 20(S)-Rg3, which reduces the expression of hypoxia-inducible factor 1α (HIF-1α) by activating the ubiquitin-proteasome pathway to promote HIF-1α degradation. A decrease in HIF-1α in turn leads to up-regulation, via transcriptional suppression of Snail, of the epithelial cell-specific marker E-cadherin and down-regulation of the mesenchymal cell-specific marker vimentin under hypoxic conditions. Importantly, 20(S)-Rg3 effectively inhibits EMT in nude mouse xenograft models of ovarian cancer, promising a novel therapeutic agent for anticancer therapy.
Ginsenoside 20(S)-Rg3 Targets HIF-1α to Block Hypoxia-Induced Epithelial-Mesenchymal Transition... - Europe PMC Article - Europe PMC
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