Antroquinonol displays anticancer potential against human hepatocellular carcinoma cells: A crucial role of AMPK and mTOR pathways

被引：107

作者：

Chiang, Po-Cheng ^{[1
]}

Lin, Ssu-Chia ^{[1
]}

Pan, Shiow-Lin ^{[2
]}

Kuo, Ching-Hua ^{[1
]}

Tsai, I-Lin ^{[1
]}

Kuo, Mao-Tien ^{[3
]}

Wen, Wu-Che ^{[3
]}

Chen, Peini ^{[4
]}

Guh, Jih-Hwa ^{[1
,5
]}

机构：

[1] Natl Taiwan Univ, Sch Pharm, Taipei 100, Taiwan

[2] Natl Taiwan Univ, Coll Med, Inst Pharmacol, Taipei 100, Taiwan

[3] Golden Biotechnol Corp, Taipei, Taiwan

[4] Taipei Vet Gen Hosp, Dept Radiol, Taipei, Taiwan

[5] Ohio State Univ, Coll Pharm, Div Med Chem, Columbus, OH 43210 USA

来源：

BIOCHEMICAL PHARMACOLOGY | 2010年 / 79卷 / 02期

关键词：

Antroquinonol; Hepatocellular carcinoma; AMPK; mTOR; G1; arrest; ACTIVATED PROTEIN-KINASE; ANTRODIA-CAMPHORATA; TUBEROUS SCLEROSIS; CANCER CELLS; PHOSPHORYLATION; PROLIFERATION; INHIBITION; RAPAMYCIN; TARGET; EXPRESSION;

D O I：

10.1016/j.bcp.2009.08.022

中图分类号：

R9 [药学];

学科分类号：

100702 [药剂学];

摘要：

5'AMP-activated protein kinase (AMPK) and the mammalian target of rapamycin (mTOR) are two serine/threonine protein kinases responsible for cellular energy homeostasis and translational control, respectively. Evidence suggests that these two kniases are potential targets for cancer chemotherapy against hepatocellular carcinoma (HCC). Antroquinonol that is isolated from Antrodia camphorate, a well-known Traditional Chinese Medicine for treatment of liver diseases, displayed effective anticancer activity against both HBV DNA-positive and -negative HCC cell lines. The rank order of potency against HCCs is HepG2 > HepG2.2.15 > Mahlavu > PLC/PRF/5 > SK-Hep1 > Hep3B. Antroquinonol completely abolished cell-cycle progression released from double-thymidine-block synchronization and caused a subsequent apoptosis. The data were supported by down-regulation and reduced nuclear translocation of G1-regulator proteins, including cyclin D1, cyclin E, Cdk4 and Cdk2. Further analysis showed that the mRNA expressions of the G1-regulator proteins were not modified by antroquinonol, indicating an inhibition of translational but not transcriptional levels. Antroquinonol induced the assembly of tuberous sclerosis complex (TSC)-1/TSC2, leading to the blockade of cellular protein synthesis through inhibition of protein phosphorylation including mTOR (Ser(2448)), p70(S6K) (Thr(421)/Ser(424) and Thr(389)) and 4E-BP1 (Thr(37)/Thr(46) and Thr(70)). Furthermore, the AMPK activity was elevated by antroquinonol. Compound C, a selective AMPK inhibitor, significantly reversed antroquinonol-mediated effects suggesting the crucial role of AMPK. Besides, the loss of mitochondrial membrane potential and depletion of mitochondrial content indicated the mitochondrial stress caused by antroquinonol. In summary, the data suggest that antroquinonol displays anticancer activity against HCCs through AMPK activation and inhibition of mTOR translational pathway, leading to G1 arrest of the cell-cycle and subsequent cell apoptosis. (C) 2009 Elsevier Inc. All rights reserved.

引用

页码：162 / 171

页数：10

共 45 条

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Activation of AMP-activated protein kinase (AMPK) inhibits protein synthesis: a potential strategy to prevent the development of cardiac hypertrophy [J].