Antroquinonol, a natural ubiquinone derivative, induces a cross talk between apoptosis, autophagy and senescence in human pancreatic carcinoma cells
| Autor: | Mao-Tien Kuo, Po-Cheng Chiang, Peini Chen, Jih-Hwa Guh, Chia-Chun Yu, Pin-Hsuan Lu, Wu-Che Wen |
|---|---|
| Rok vydání: | 2011 |
| Předmět: |
Programmed cell death
Ubiquinone Endocrinology Diabetes and Metabolism Clinical Biochemistry Apoptosis Biology Biochemistry chemistry.chemical_compound Cell Line Tumor Autophagy Humans Propidium iodide Molecular Biology Protein kinase B PI3K/AKT/mTOR pathway Cellular Senescence Nutrition and Dietetics Cell Death Cell growth TOR Serine-Threonine Kinases Cell Cycle Cell cycle Cell biology Pancreatic Neoplasms chemistry Proto-Oncogene Proteins c-akt |
| Zdroj: | The Journal of nutritional biochemistry. 23(8) |
| ISSN: | 1873-4847 |
| Popis: | 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 Ser(473), the phosphorylation site critical for Akt kinase activity, and blocked the mammalian target of rapamycin (mTOR) phosphorylation at Ser(2448), 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 p21(Waf1/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. |
| Databáze: | OpenAIRE |
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