|Title:||Antroquinonol, a natural ubiquinone derivative, induces a cross talk between apoptosis, autophagy and senescence in human pancreatic carcinoma cells||Authors:||Yu C.-C.
|Keywords:||Akt; Bcl-xL; K-ras; MTOR; Pancreatic cancer||Issue Date:||2012||Journal Volume:||23||Journal Issue:||8||Start page/Pages:||900-907||Source:||Journal of Nutritional Biochemistry||Abstract:||
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. ? 2012 Elsevier Inc.
|ISSN:||9552863||DOI:||10.1016/j.jnutbio.2011.04.015||SDG/Keyword:||antineoplastic agent; antroquinonol; cyclin dependent kinase inhibitor 1; K ras protein; mammalian target of rapamycin; propidium iodide; protein Bak; protein Bax; protein bcl xl; protein kinase B; protein mcl 1; serine; ubiquinone derivative; unclassified drug; antineoplastic activity; apoptosis; article; autophagy; carcinoma cell; cell cycle G1 phase; cell death; cell proliferation; concentration response; controlled study; DNA content; down regulation; enzyme activity; enzyme phosphorylation; flow cytometry; human; human cell; mitochondrial membrane potential; pancreas carcinoma; protein expression; senescence; signal transduction; Apoptosis; Autophagy; Cell Aging; Cell Cycle; Cell Death; Cell Line, Tumor; Humans; Pancreatic Neoplasms; Proto-Oncogene Proteins c-akt; TOR Serine-Threonine Kinases; Ubiquinone; Basidiomycota; Cinnamomum camphora; Mammalia; Taiwanofungus camphoratus
|Appears in Collections:||藥學系|
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