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Sci.Rep:中科院近代物理所张红研究组发表肿瘤细胞凋亡机理获新进展

摘要 : 近日,自然出版集团旗下综合类刊物《Scientific Reports》在线发表中国科学院近代物理所张红研究组的一篇研究论文,研究人员利用兰州重离子研究装置(HIRFL)提供的碳离子束,研究高LET射线诱导肿瘤细胞的凋亡分子机理获得新发现。

 近日,自然出版集团旗下综合类刊物《Scientific Reports》在线发表中国科学院近代物理所张红研究组的一篇研究论文,研究人员利用兰州重离子研究装置(HIRFL)提供的碳离子束,研究高LET射线诱导肿瘤细胞的凋亡分子机理获得新发现。

细胞凋亡是电离辐射所致细胞死亡的主要形式。p73是p53家族蛋白成员之一,在人类肿瘤细胞中很少发生缺失或突变,反而呈现出很高量的表达。p73是抑制凋亡基因还是促进凋亡基因这个问题仍处于争论之中。p73有两组蛋白异构体:Tap73和NP73。Tap73和ΔNP73被誉为肿瘤生死存亡的“开关”。目前对于p73异构体在高LET射线诱导的肿瘤细胞凋亡中的作用机制尚未见报道。

张红研究组发现,碳离子辐射诱导肿瘤细胞G2/M期阻滞,抑制其生长和增殖,并明显促进了肿瘤细胞凋亡(如图1所示)。其机理为:电离辐射通过激活p73基因的选择性剪接,启动p73介导的死亡受体和线粒体凋亡信号通路,进而促进了肿瘤细胞凋亡的发生(如图2所示)。此外,大蒜的天然活性产物二烯丙基二硫(Diallyl disulfide,简称DADS),不但能够提高肿瘤细胞的辐射敏感性,而且对正常细胞具有辐射保护作用。 进一步的实验证实: DADS协同碳离子,通过上调癌细胞Tap73/ΔNP73, 激活凋亡信号通路,促进了癌细胞凋亡;而对于正常细胞,则通过下调Tap73/ΔNP73, 抑制其凋亡信号途径,并促进DNA损伤的修复。这些发现首次揭示了高LET射线诱导肿瘤细胞凋亡新的分子机理,有可能为提高重离子放疗效果及阐明其安全性机理提供新思路。

图1 碳离子将恶性肿瘤细胞周期阻滞于G2/M期,抑制其生长,并明显诱导了肿瘤细胞凋亡。

图2 碳离子通过启动凋亡开关“Tap73和ΔNP73”,进而促进了恶性肿瘤细胞凋亡的发生。

原文链接:

Diallyl disulfide attenuated carbon ion irradiation-induced apoptosis in mouse testis through changing the ratio of Tap73/ΔNp73 via mitochondrial pathway

原文摘要:

Diallyl disulfide (DADS), a major organosulfur compound derived from garlic, has various biological properties, including anti-cancer effects. However, the protective mechanism of DADS against radiation-induced mouse testis cell apoptosis has not been elucidated. In this study, the magnitude of radiation effects evoked by carbon ion irradiation was marked by morphology changes, significant rise in apoptotic cells, activation expression of p53, up regulation the ratio of pro-apoptotic Tap73/anti-apoptotic ΔNp73, as well as alterations of crucial mediator of the mitochondrial pathway. Interestingly, pretreatment with DADS attenuated carbon ion irradiation-induced morphology damages and apoptotic cells. Additionally, DADS elevated radiation-induced p53 and p21 expression, suggesting that p53 might be involved in the inhibition of cell cycle progression through up regulation of p21. Furthermore, administration with DADS prevented radiation-induced Tap73/ΔNp73 expression and consequently down regulated Bax/Bcl-2 ratio, cytochrome c release and caspase-3 expression, indicating that the balance between Tap73 and ΔNp73 had potential to activate p53 responsive genes. Thus, our results showed that radio protection effect of DADS on mouse testis is mediated by blocking apoptosis through changing the ratio of Tap73/ΔNp73 via mitochondrial pathway, suggesting that DADS could be used as a potential radio protection agent for the testis against heavy-ion radiation.

来源: Scientific Reports 浏览次数:0

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