Dihydrotanshinone I inhibits the translational expression of hypoxia-inducible factor-1α.
The hypoxia-inducible factor-1 (HIF-1) has been known to be correlated to the adaptation and proliferation of tumor cells; therefore HIF-1 has become an important target in the development of anticancer drugs. Dihydrotanshinone I (DHTS) is a phenanthrenequinone compound from Salvia miltiorrhiza Bunge, which has been used in oriental medicine for its antitumor activities. However, the mechanisms by which DHTS inhibits tumor growth are not fully understood. We here demonstrated the effect of DHTS on hypoxia-inducible factor-1 (HIF-1) activation. DHTS dose-dependently decreased the hypoxia-induced accumulation and activation of HIF-1α protein. Further analysis revealed that DHTS inhibited HIF-1α protein synthesis, without affecting the expression level of HIF-1α mRNA or degradation of HIF-1α protein. Moreover, the phosphorylation levels of mammalian target of rapamycin (mTOR), extracellular signal-regulated kinase-1/2 (ERK1/2), ribosomal protein S6 kinase (p70S6K), eIF4E binding protein-1 (4E-BP1), and eukaryotic initiation factor 4E (eIF4E) were dose-dependently suppressed by DHTS, but no significant effect on total protein levels was observed. Furthermore, DHTS prevented hypoxia-induced expression of HIF-1 target genes and flow cytometric analysis indicated that DHTS induced G1 phase arrest in HeLa cell. In vivo studies further confirmed the inhibitory effect of DHTS on the expression of HIF-1α proteins, leading to a decrease in growth of HeLa cells in a xenograft tumor model. These results show that DHTS inhibited HIF-1α protein synthesis by downregulating the mTOR/p70S6K/4E-BP1 and MEK/ERK pathways. These conclusions suggest that DHTS is an effective inhibitor of HIF-1 and provide new perspectives into the mechanism of its anticancer activity.
Key Laboratory of Natural Resources of Changbai Mountain & Functional Molecules, Ministry of Education, Department of Chemistry, College of Pharmacy, Molecular Medicine Research Center, Yanbian University, Yanji 133002, Jilin Province, China.
Jing
J
Li
Key Laboratory of Natural Resources of Changbai Mountain & Functional Molecules, Ministry of Education, Department of Chemistry, College of Pharmacy, Molecular Medicine Research Center, Yanbian University, Yanji 133002, Jilin Province, China.
Chunliu
C
Mi
Key Laboratory of Natural Resources of Changbai Mountain & Functional Molecules, Ministry of Education, Department of Chemistry, College of Pharmacy, Molecular Medicine Research Center, Yanbian University, Yanji 133002, Jilin Province, China.
Juan
J
Ma
Key Laboratory of Natural Resources of Changbai Mountain & Functional Molecules, Ministry of Education, Department of Chemistry, College of Pharmacy, Molecular Medicine Research Center, Yanbian University, Yanji 133002, Jilin Province, China.
Ke Si
KS
Wang
Key Laboratory of Natural Resources of Changbai Mountain & Functional Molecules, Ministry of Education, Department of Chemistry, College of Pharmacy, Molecular Medicine Research Center, Yanbian University, Yanji 133002, Jilin Province, China.
Jung Joon
JJ
Lee
Key Laboratory of Natural Resources of Changbai Mountain & Functional Molecules, Ministry of Education, Department of Chemistry, College of Pharmacy, Molecular Medicine Research Center, Yanbian University, Yanji 133002, Jilin Province, China. Electronic address: xjjin@ybu.edu.cn.
Xuejun
X
Jin
D000970:Antineoplastic Agents / Q000494:pharmacology; D049109:Cell Proliferation / Q000187:drug effects; D005663:Furans; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation / Q000187:drug effects*; D006367:HeLa Cells; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism; D010616:Phenanthrenes / Q000494:pharmacology*; D016133:Polymerase Chain Reaction; D011809:Quinones; D015398:Signal Transduction / Q000187:drug effects
D000970:Antineoplastic Agents; D005663:Furans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D010616:Phenanthrenes; D011809:Quinones; C000713095:dihydrotanshinone I
Anticancer; Dihydrotanshinone I (DHTS); ERK1/2; HIF-1; mTOR