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首页> 外文期刊>The Journal of Nutritional Biochemistry >Antroquinonol, a natural ubiquinone derivative, induces a cross talk between apoptosis, autophagy and senescence in human pancreatic carcinoma cells.
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Antroquinonol, a natural ubiquinone derivative, induces a cross talk between apoptosis, autophagy and senescence in human pancreatic carcinoma cells.

机译：蒽醌是一种天然的泛醌衍生物，可诱导人胰腺癌细胞凋亡，自噬和衰老之间发生串扰。

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摘要

Pancreatic cancer is a malignant neoplasm of the pancreas. A mutation and constitutive activation of K-ras occurs in more than 90% of pancreatic adenocarcinomas. A successful approach for the treatment of pancreatic cancers is urgent. Antroquinonol, a ubiquinone derivative isolated from a camphor tree mushroom, Antrodia camphorata, induced a concentration-dependent inhibition of cell proliferation in pancreatic cancer PANC-1 and AsPC-1 cells. Flow cytometric analysis of DNA content by propidium iodide staining showed that antroquinonol induced G1 arrest of the cell cycle and a subsequent apoptosis. Antroquinonol inhibited Akt phosphorylation at Ser473, the phosphorylation site critical for Akt kinase activity, and blocked the mammalian target of rapamycin (mTOR) phosphorylation at Ser2448, a site dependent on mTOR activity. Several signals responsible for mTOR/p70S6K/4E-BP1 signaling cascades have also been examined to validate the pathway. Moreover, antroquinonol induced the down-regulation of several cell cycle regulators and mitochondrial antiapoptotic proteins. In contrast, the expressions of K-ras and its phosphorylation were significantly increased. The coimmunoprecipitation assay showed that the association of K-ras and Bcl-xL was dramatically augmented, which was indicative of apoptotic cell death. Antroquinonol also induced the cross talk between apoptosis, autophagic cell death and accelerated senescence, which was, at least partly, explained by the up-regulation of p21Waf1/Cip1 and K-ras. In summary, the data suggest that antroquinonol induces anticancer activity in human pancreatic cancers through an inhibitory effect on PI3-kinase/Akt/mTOR pathways that in turn down-regulates cell cycle regulators. The translational inhibition causes G1 arrest of the cell cycle and an ultimate mitochondria-dependent apoptosis. Moreover, autophagic cell death and accelerated senescence also explain antroquinonol-mediated anticancer effect.
机译：胰腺癌是胰腺的恶性肿瘤。超过90％的胰腺腺癌发生K-ras突变和组成性激活。成功的胰腺癌治疗方法迫在眉睫。从樟树蘑菇樟芝中分离得到的泛醌衍生物蒽醌可诱导胰腺癌PANC-1和AsPC-1细胞中细胞增殖的浓度依赖性抑制作用。通过碘化丙啶染色对DNA含量进行流式细胞术分析，结果表明蒽醌引起细胞周期的G1阻滞和随后的细胞凋亡。蒽醌抑制对Akt激酶活性至关重要的磷酸化位点Ser 473 的Akt磷酸化，并阻断哺乳动物对雷帕霉素（mTOR）磷酸化的靶标Ser 2448 的磷酸化目标mTOR活动。还已经对负责mTOR / p70S6K / 4E-BP1信号级联反应的几种信号进行了验证，以验证该途径。此外，蒽醌诱导几种细胞周期调节因子和线粒体抗凋亡蛋白的下调。相反，K-ras的表达及其磷酸化显着增加。免疫共沉淀试验表明，K-ras和Bcl-xL的结合显着增强，这表明细胞凋亡。喹诺酮还引起细胞凋亡，自噬细胞死亡和衰老加速之间的交互作用，这至少部分是由于p21 Waf1 / Cip1 和K-ras的上调所致。总而言之，数据表明蒽醌通过对PI3激酶/ Akt / mTOR通路的抑制作用诱导人类胰腺癌的抗癌活性，进而抑制细胞周期调节因子。翻译抑制导致细胞周期的G1阻滞和最终的线粒体依赖性细胞凋亡。此外，自噬细胞的死亡和衰老的加速也解释了蒽醌介导的抗癌作用。

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