J Cancer Prev.  2018 Jun;23(2):63-69. 10.15430/JCP.2018.23.2.63.

Anti-proliferative Effect of 15,16-Dihydrotanshinone I Through Cell Cycle Arrest and the Regulation of AMP-activated Protein Kinase/Akt/mTOR and Mitogen-activated Protein Kinase Signaling Pathway in Human Hepatocellular Carcinoma Cells

Affiliations
  • 1College of Pharmacy, Seoul National University, Seoul, Korea. sklee61@snu.ac.kr

Abstract

BACKGROUND
15,16-dihydrotanshinone I (DHTS) is a natural abietane diterpenoid that is mainly found in the roots of Salvia miltiorrhiza Bunge (Labiatae). DHTS exhibits a potential anti-proliferative effect in various human cancer cells. However, the mechanisms of action of DHTS as an anti-cancer agent have not been fully elucidated. Therefore, the present study investigated the anti-cancer effect of DHTS in terms of cell cycle regulation and the regulation of the AMP-activated protein kinase (AMPK)/Akt/mTOR signaling pathway in SK-HEP-1 human hepatocellular carcinoma cells.
METHODS
The anti-proliferative effects of DHTS were evaluated by the sulforhodamine B assay in SK-HEP-1 cells. Cell cycle distribution was analyzed by flow cytometry. The elucidation of mechanisms of action such as the AMPK/AKT/mTOR and mitogen-activated protein kinase (MAPK) pathway was assessed by Western blot analysis.
RESULTS
DHTS showed a significant anti-proliferative activity against SK-HEP-1 cells. DHTS induced cell cycle arrest in the G0/G1 phase, which was mediated by downregulation of cyclin D1, cyclin A, cyclin E, CDK4, CDK2, c-Myc and p-Rb expression and with increased expression of the CDK inhibitor p21. DHTS also activated the AMPK signaling. In addition, DHTS downregulated the Akt/mTOR and MAPK signaling pathways.
CONCLUSIONS
Our results suggest that the anti-proliferative activity of DHTS might be associated with the induction of G0/G1 phase cell cycle arrest and regulation of AMPK/Akt/mTOR and MAPK signaling pathways in SK-HEP-1 cells.

Keyword

15,16-Dihydrotanshinone I; Salvia miltiorrhiza; Cell cycle arrest; AMP-activated protein kinase; Hepatocellular carcinoma

MeSH Terms

AMP-Activated Protein Kinases
Blotting, Western
Carcinoma, Hepatocellular*
Cell Cycle Checkpoints*
Cell Cycle*
Cyclin A
Cyclin D1
Cyclin E
Cyclins
Down-Regulation
Flow Cytometry
Humans*
Protein Kinases*
Salvia miltiorrhiza
AMP-Activated Protein Kinases
Cyclin A
Cyclin D1
Cyclin E
Cyclins
Protein Kinases
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