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
10.15430/JCP.2018.23.2.63
- Author:
Ji Young HONG
1
;
So Hyun PARK
;
Hyen Joo PARK
;
Sang Kook LEE
Author Information
1. College of Pharmacy, Seoul National University, Seoul, Korea. sklee61@snu.ac.kr
- Publication Type:Original Article
- Keywords:
15,16-Dihydrotanshinone I;
Salvia miltiorrhiza;
Cell cycle arrest;
AMP-activated protein kinase;
Hepatocellular carcinoma
- MeSH:
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
- From:Journal of Cancer Prevention
2018;23(2):63-69
- CountryRepublic of Korea
- Language:English
-
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.
