Wogonin has multiple anti-cancer effects by regulating c-Myc/SKP2/Fbw7α and HDAC1/HDAC2 pathways and inducing apoptosis in human lung adenocarcinoma cell line A549

• Published in: PloS one 2013-11, Vol.8 (11), p.e79201
• Main Authors: Chen, Xin-mei, Bai, Yang, Zhong, Yu-jian, Xie, Xiao-lin, Long, Han-wu, Yang, Yu-yin, Wu, Shi-gen, Jia, Qiang, Wang, Xiao-hua
• Format: Article
• Language: English
• Subjects: Adenocarcinoma; Adenocarcinoma - genetics; Adenocarcinoma - metabolism; Adenocarcinoma of Lung; Angiogenesis; Anticancer properties; Apoptosis; Apoptosis - drug effects; Apoptosis-inducing factor; Biology; Breast cancer; c-Myc protein; Cancer; Cell adhesion & migration; Cell Cycle - drug effects; Cell Cycle Proteins - metabolism; Cell Line, Tumor; Cell Proliferation - drug effects; Cell Survival - drug effects; Change detection; Cyclin-dependent kinases; Degradation; Drug resistance; Enzymes; Exposure; F-Box Proteins - metabolism; F-Box-WD Repeat-Containing Protein 7; Flavanones - pharmacology; Gene expression; Gene Expression Regulation, Neoplastic - drug effects; Glycogen Synthase Kinase 3 - metabolism; Glycogen Synthase Kinase 3 beta; HDAC2 protein; Histone deacetylase; Histone Deacetylase 1 - genetics; Histone Deacetylase 1 - metabolism; Histone Deacetylase 2 - genetics; Histone Deacetylase 2 - metabolism; Humans; Immunoglobulins; Kinases; Leukemia; Ligands; Liver cancer; Lung cancer; Lung Neoplasms - genetics; Lung Neoplasms - metabolism; Mcl-1 protein; Medical research; Membrane Potential, Mitochondrial; mRNA; Multiple myeloma; Myc protein; Phosphorylation; Poly(ADP-ribose) polymerase; Proteins; 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; Skp2 protein; Tumor necrosis factor-TNF; Tumors; Ubiquitin; Ubiquitin-Protein Ligases - metabolism; Viability; XIAP protein
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0079201

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.