Modulation of oxidative stress and subsequent induction of apoptosis and endoplasmic reticulum stress allows citral to decrease cancer cell proliferation.
Modulation of oxidative stress and subsequent induction of apoptosis and endoplasmic reticulum stress allows citral to decrease cancer cell proliferation.
复制标题
氧化应激的调节以及随后诱导的凋亡和内质网应激使柠檬质减少癌细胞增殖。
DOI：
10.1038/srep27530
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发表时间：
2016-06-08
影响因子：
4.6
通讯作者：
Patankar MS
中科院分区：
文献类型：
--
作者：
Kapur A;Felder M;Fass L;Kaur J;Czarnecki A;Rathi K;Zeng S;Osowski KK;Howell C;Xiong MP;Whelan RJ;Patankar MS
当通过PEG-b-PCL纳米颗粒递送时，单萜类化合物柠檬醛抑制4 T1乳腺肿瘤的体内生长。在这里，我们表明柠檬醛抑制多种人类癌细胞系的增殖。在表达p53的ECC-1和OVCAR-3细胞中，柠檬醛诱导G1/S期细胞周期阻滞和凋亡，通过膜联蛋白V染色测定，并增加切割的半胱天冬酶3和Bax，减少Bcl-2，但在p53缺陷的SKOV-3细胞中不诱导。在SKOV-3细胞中，柠檬醛诱导ER应激标志物CHOP、GADD 45、EDEM、ATF 4、Hsp 90、ATG 5和磷酸化eIF 2 α。分子伴侣4-苯基丁酸在SKOV-3中减弱柠檬醛活性，但在ECC-1和OVCAR-3细胞中不减弱。在表达p53的细胞中，柠檬醛增加p53的丝氨酸-15的磷酸化。p53的激活增加Bax、BRA和NOXA的表达。pifithrin-α抑制p53，减弱柠檬醛介导的细胞凋亡。柠檬醛增加细胞内氧自由基，这导致p53的激活。通过L-丁硫氨酰亚砜胺抑制谷胱甘肽合成增加柠檬醛的效力。用N-乙酰半胱氨酸预处理降低柠檬醛处理的ECC-1和OVCAR-3中p53的磷酸化。这些结果定义了柠檬醛的p53依赖性和在p53不存在的情况下的ER应激依赖性作用模式。该研究表明，PEG-b-PCL纳米颗粒制剂中的柠檬醛应考虑用于治疗乳腺癌和其他肿瘤。
The monoterpenoid, citral, when delivered through PEG-b-PCL nanoparticles inhibits in vivo growth of 4T1 breast tumors. Here, we show that citral inhibits proliferation of multiple human cancer cell lines. In p53 expressing ECC-1 and OVCAR-3 but not in p53-deficient SKOV-3 cells, citral induces G1/S cell cycle arrest and apoptosis as determined by Annexin V staining and increased cleaved caspase3 and Bax and decreased Bcl-2. In SKOV-3 cells, citral induces the ER stress markers CHOP, GADD45, EDEM, ATF4, Hsp90, ATG5, and phospho-eIF2α. The molecular chaperone 4-phenylbutyric acid attenuates citral activity in SKOV-3 but not in ECC-1 and OVCAR-3 cells. In p53-expressing cells, citral increases phosphorylation of serine-15 of p53. Activation of p53 increases Bax, PUMA, and NOXA expression. Inhibition of p53 by pifithrin-α, attenuates citral-mediated apoptosis. Citral increases intracellular oxygen radicals and this leads to activation of p53. Inhibition of glutathione synthesis by L-buthionine sulfoxamine increases potency of citral. Pretreatment with N-acetylcysteine decreases phosphorylation of p53 in citral-treated ECC-1 and OVCAR-3. These results define a p53-dependent, and in the absence of p53, ER stress-dependent mode of action of citral. This study indicates that citral in PEG-b-PCL nanoparticle formulation should be considered for treatment of breast and other tumors.