Induction of ROS Overload by Alantolactone Prompts Oxidative DNA Damage and Apoptosis in Colorectal Cancer Cells.
Induction of ROS Overload by Alantolactone Prompts Oxidative DNA Damage and Apoptosis in Colorectal Cancer Cells.
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DOI：
10.3390/ijms17040558
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发表时间：
2016-04-14
影响因子：
5.6
通讯作者：
Cheng Y
中科院分区：
文献类型：
--
作者：
Ding Y;Wang H;Niu J;Luo M;Gou Y;Miao L;Zou Z;Cheng Y
癌细胞通常表现出高于正常水平的活性氧（ROS），这可能促进癌症的发展和进展，但也可能使癌细胞更容易受到进一步的ROS损伤。事实上，目前的许多抗癌疗法通过诱导氧化应激来杀死癌细胞，尽管它们靶向癌症和正常细胞。近年来，研究表明，土木香内酯（ATL）可通过增加癌细胞内ROS水平诱导细胞凋亡，但其与细胞凋亡的分子机制尚不清楚。在这里，我们表明，ATL诱导的ROS过载在人SW 480和SW 1116结直肠癌细胞中，随后是细胞氧化鸟嘌呤（8-oxoG）的显著积累和DNA链断裂数量的立即增加，表明ROS增加导致广泛的氧化DNA损伤。因此，G1/S-CDK抑制剂CDKN 1B（p21）和促凋亡蛋白Bax和活化的caspase-3上调，而抗凋亡蛋白Bcl-2下调，随后细胞周期停滞在G1期，并在ATL处理的癌细胞中发生显著的凋亡，而非癌细胞则没有。这些结果表明，ATL诱导的ROS过载通过诱导大量的氧化性DNA损伤和随后的内在凋亡途径的激活来触发细胞死亡。
Cancer cells typically display higher than normal levels of reactive oxygen species (ROS), which may promote cancer development and progression but may also render the cancer cells more vulnerable to further ROS insult. Indeed, many of the current anticancer therapeutics kill cancer cells via induction of oxidative stress, though they target both cancer and normal cells. Recently, alantolactone (ATL), a natural sesquiterpene lactone, has been shown to induce apoptosis by increasing ROS levels specifically in cancer cells; however, the molecular mechanisms linking ROS overproduction to apoptosis remain unclear. Here we show that the ATL-induced ROS overload in human SW480 and SW1116 colorectal cancer cells was followed by a prominent accumulation of cellular oxidized guanine (8-oxoG) and immediate increase in the number of DNA strand breaks, indicating that increased ROS resulted in extensive oxidative DNA damage. Consequently, the G1/S-CDK suppresser CDKN1B (p21) and pro-apoptotic proteins Bax and activated caspase-3 were upregulated, while anti-apoptotic Bcl-2 was downregulated, which were followed by cell cycle arrest at G1 and marked apoptosis in ATL-treated cancer but not non-cancer cells. These results suggest that the ATL-induced ROS overload triggers cell death through induction of massive oxidative DNA damage and subsequent activation of the intrinsic apoptosis pathway.