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

Po Cheng Chiang, Ssu Chia Lin, Shiow Lin Pan, Ching Hua Kuo, I. Lin Tsai, Mao Tien Kuo, Wu Che Wen, Peini Chen, Jih Hwa Guh

Research output: Contribution to journalArticle

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Abstract

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 (Ser2448), p70S6K (Thr421/Ser424 and Thr389) and 4E-BP1 (Thr37/Thr46 and Thr70). 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.

Original languageEnglish
Pages (from-to)162-171
Number of pages10
JournalBiochemical Pharmacology
Volume79
Issue number2
DOIs
Publication statusPublished - Jan 15 2010
Externally publishedYes

Fingerprint

AMP-Activated Protein Kinases
Sirolimus
Hepatocellular Carcinoma
Display devices
Cells
Antrodia
Proteins
Apoptosis
70-kDa Ribosomal Protein S6 Kinases
G1 Phase Cell Cycle Checkpoints
Cyclin E
Phosphorylation
Tuberous Sclerosis
Chemotherapy
antroquinonol
Mitochondrial Membrane Potential
Protein-Serine-Threonine Kinases
Cyclin D1
Chinese Traditional Medicine
Programmable logic controllers

Keywords

  • AMPK
  • Antroquinonol
  • G1 arrest
  • Hepatocellular carcinoma
  • mTOR

ASJC Scopus subject areas

  • Pharmacology
  • Biochemistry

Cite this

Antroquinonol displays anticancer potential against human hepatocellular carcinoma cells : A crucial role of AMPK and mTOR pathways. / Chiang, Po Cheng; Lin, Ssu Chia; Pan, Shiow Lin; Kuo, Ching Hua; Tsai, I. Lin; Kuo, Mao Tien; Wen, Wu Che; Chen, Peini; Guh, Jih Hwa.

In: Biochemical Pharmacology, Vol. 79, No. 2, 15.01.2010, p. 162-171.

Research output: Contribution to journalArticle

Chiang, Po Cheng ; Lin, Ssu Chia ; Pan, Shiow Lin ; Kuo, Ching Hua ; Tsai, I. Lin ; Kuo, Mao Tien ; Wen, Wu Che ; Chen, Peini ; Guh, Jih Hwa. / Antroquinonol displays anticancer potential against human hepatocellular carcinoma cells : A crucial role of AMPK and mTOR pathways. In: Biochemical Pharmacology. 2010 ; Vol. 79, No. 2. pp. 162-171.
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AU - Tsai, I. Lin

AU - Kuo, Mao Tien

AU - Wen, Wu Che

AU - Chen, Peini

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