Abstract
Wogonin is a plant monoflavonoid which has been reported to inhibit cell growth and/or induce apoptosis in various tumors. The present study examined the apoptosis-inducing activity and underlying mechanism of action of wogonin in A549 cells. The results showed that wogonin was a potent inhibitor of the viability of A549 cells. Apoptotic protein changes detected after exposure to wogonin included decreased XIAP and Mcl-1 expression, increased cleaved-PARP expression and increased release of AIF and cytochrome C. Western blot analysis showed that the activity of c-Myc/Skp2 and HDAC1/HDAC2 pathways, which play important roles in tumor progress, was decreased. Quantitative PCR identified increased levels of c-Myc mRNA and decreased levels of its protein. Protein levels of Fbw7α, GSK3β and Thr58-Myc, which are involved in c-Myc ubiquitin-dependent degradation, were also analyzed. After exposure to wogonin, Fbw7α and GSK3β expression decreased and Thr58-Myc expression increased. However, MG132 was unable to prevent c-Myc degradation. The present results suggest that wogonin has multiple anti-cancer effects associated with degradation of c-Myc, SKP2, HDAC1 and HDAC2. Its ability to induce apoptosis independently of Fbw7α suggests a possible use in drug-resistance cancer related to Fbw7 deficiency. Further studies are needed to determine which pathways are related to c-Myc and Fbw7α reversal and whether Thr58 phosphorylation of c-Myc is dependent on GSK3β.
Publication types
-
Research Support, Non-U.S. Gov't
MeSH terms
-
Adenocarcinoma / genetics
-
Adenocarcinoma / metabolism*
-
Adenocarcinoma of Lung
-
Apoptosis / drug effects*
-
Cell Cycle / drug effects
-
Cell Cycle Proteins / metabolism*
-
Cell Line, Tumor
-
Cell Proliferation / drug effects
-
Cell Survival / drug effects
-
F-Box Proteins / metabolism*
-
F-Box-WD Repeat-Containing Protein 7
-
Flavanones / pharmacology*
-
Gene Expression Regulation, Neoplastic / drug effects
-
Glycogen Synthase Kinase 3 / metabolism
-
Glycogen Synthase Kinase 3 beta
-
Histone Deacetylase 1 / genetics
-
Histone Deacetylase 1 / metabolism*
-
Histone Deacetylase 2 / genetics
-
Histone Deacetylase 2 / metabolism*
-
Humans
-
Lung Neoplasms / genetics
-
Lung Neoplasms / metabolism*
-
Membrane Potential, Mitochondrial
-
Proto-Oncogene Proteins c-myc / genetics
-
Proto-Oncogene Proteins c-myc / metabolism*
-
RNA, Messenger / genetics
-
RNA, Messenger / metabolism
-
S-Phase Kinase-Associated Proteins / metabolism*
-
Signal Transduction / drug effects*
-
Ubiquitin-Protein Ligases / metabolism*
Substances
-
Cell Cycle Proteins
-
F-Box Proteins
-
F-Box-WD Repeat-Containing Protein 7
-
FBXW7 protein, human
-
Flavanones
-
Proto-Oncogene Proteins c-myc
-
RNA, Messenger
-
S-Phase Kinase-Associated Proteins
-
Ubiquitin-Protein Ligases
-
GSK3B protein, human
-
Glycogen Synthase Kinase 3 beta
-
Glycogen Synthase Kinase 3
-
Histone Deacetylase 1
-
Histone Deacetylase 2
-
wogonin
Grants and funding
The study was supported by grants from the Ministry of Science and Technology of Guizhou Province, China ([2012] 7006 and NY [2011]3072); Guangzhou Medical College (2012C16); the Foundation for Young Scientists of Guangzhou Educational Committee (2012C118). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.