PMID- 24766860
OWN - NLM
STAT- MEDLINE
DCOM- 20140826
LR  - 20211021
IS  - 1756-9966 (Electronic)
IS  - 0392-9078 (Print)
IS  - 0392-9078 (Linking)
VI  - 33
IP  - 1
DP  - 2014 Apr 26
TI  - p38alpha MAPK-mediated induction and interaction of FOXO3a and p53 contribute to the 
      inhibited-growth and induced-apoptosis of human lung adenocarcinoma cells by 
      berberine.
PG  - 36
LID - 10.1186/1756-9966-33-36 [doi]
AB  - BACKGROUND: Berberine (BBR), a component from traditional Chinese medicine, has 
      been shown to possess anti-tumor activity against a wide spectrum of cancer cells 
      including human lung cancer, but the detailed mechanism underlining this has not 
      been well elucidated. METHODS: In this study, the effect of berberine on cell 
      growth and apoptosis were assessed by MTT, flow cytometry and Hoechst 33258 
      staining assays. The phosphorylation of p38 MAPK and ERK1/2, and expressions of 
      p38 MAPK isoforms alpha and beta, total ERK1/2, p53, FOXO3a and p21 protein were 
      evaluated by Western Blot analysis. Silencing of p38 MAPK isoform alpha and beta, p53, 
      FOXO3a and p21 were performed by siRNA methods. Exogenous expression of FOXO3a 
      was carried out by electroporated transfection assays. RESULTS: We showed that 
      BBR significantly inhibited growth and induced cell cycle arrest of non small 
      cell lung cancer (NSCLC) cells in the G0/G1 phase in a dose-dependent manner. 
      Furthermore, we found that BBR increased phosphorylation of p38 MAPK and ERK1/2 
      in a time-dependent and induced protein expression of tumor suppressor p53 and 
      transcription factor FOXO3a in a dose-dependent fashion. The specific inhibitor 
      of p38 MAPK (SB203580), and silencing of p38alpha MAPK by small interfering RNAs 
      (siRNAs), but not ERK1/2 inhibitor (PD98059) blocked the stimulatory effects of 
      BBR on protein expression of p53 and FOXO3a. Interestingly, inhibition of p53 
      using one specific inhibitor (Pifithrin-alpha) and silencing of p53 using siRNAs 
      overcome the inhibitory effect of BBR on cell growth. Silencing of FOXO3a 
      appeared to attenuate the effect of BBR on p53 expression, cell proliferation and 
      apoptosis. Furthermore, BBR induces the protein expression of cell cycle 
      inhibitor p21 (CIP1/WAF1), which was not observed in cells silencing of p53 or 
      FOXO3alpha gene. Intriguingly, exogenous expression of FOXO3a enhanced the expression 
      of p21 (CIP1/WAF1) and strengthened BBR-induced apoptosis. CONCLUSION: Our 
      results show that BBR inhibits proliferation and induces apoptosis of NSCLC cells 
      through activation of p38alpha MAPK signaling pathway, followed by induction of the 
      protein expression of p53 and FOXO3a. The latter contribute to the BBR-increased 
      p21 (CIP1/WAF1) protein expression. The exogenous FOXO3a, interaction and 
      mutually exclusive events of p53 and FOXO3a augment the overall response of BBR.
FAU - Zheng, Fang
AU  - Zheng F
FAU - Tang, Qin
AU  - Tang Q
FAU - Wu, JingJing
AU  - Wu J
FAU - Zhao, ShunYu
AU  - Zhao S
FAU - Liang, ZhanYang
AU  - Liang Z
FAU - Li, Liuning
AU  - Li L
FAU - Wu, WanYin
AU  - Wu W
FAU - Hann, Swei
AU  - Hann S
AD  - Laboratory of Tumor Molecular Biology and Targeted Therapies of Chinese Medicine, 
      4th Floor, Scientific Research Building, Neihuan West Road No, 55, University 
      City, Panyu District, Guangzhou, Guangdong Province, P, R, China, 510006. 
      swhan2010@live.com.
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20140426
PL  - England
TA  - J Exp Clin Cancer Res
JT  - Journal of experimental & clinical cancer research : CR
JID - 8308647
RN  - 0 (Antineoplastic Agents)
RN  - 0 (Cyclin-Dependent Kinase Inhibitor p21)
RN  - 0 (FOXO3 protein, human)
RN  - 0 (Forkhead Box Protein O3)
RN  - 0 (Forkhead Transcription Factors)
RN  - 0 (TP53 protein, human)
RN  - 0 (Tumor Suppressor Protein p53)
RN  - 0I8Y3P32UF (Berberine)
RN  - EC 2.7.11.24 (Mitogen-Activated Protein Kinase 14)
SB  - IM
MH  - Adenocarcinoma
MH  - Adenocarcinoma of Lung
MH  - Antineoplastic Agents/*pharmacology
MH  - *Apoptosis
MH  - Berberine/*pharmacology
MH  - Cell Line, Tumor
MH  - Cell Proliferation
MH  - Cyclin-Dependent Kinase Inhibitor p21/genetics/metabolism
MH  - Forkhead Box Protein O3
MH  - Forkhead Transcription Factors/genetics/*metabolism
MH  - G1 Phase Cell Cycle Checkpoints/drug effects
MH  - Gene Expression
MH  - Gene Expression Regulation, Neoplastic/drug effects
MH  - Humans
MH  - Lung Neoplasms
MH  - MAP Kinase Signaling System
MH  - Mitogen-Activated Protein Kinase 14/*physiology
MH  - Phosphorylation
MH  - Protein Processing, Post-Translational
MH  - Transcriptional Activation
MH  - Tumor Suppressor Protein p53/genetics/*metabolism
PMC - PMC4013801
EDAT- 2014/04/29 06:00
MHDA- 2014/08/27 06:00
PMCR- 2014/04/26
CRDT- 2014/04/29 06:00
PHST- 2013/12/30 00:00 [received]
PHST- 2014/04/14 00:00 [accepted]
PHST- 2014/04/29 06:00 [entrez]
PHST- 2014/04/29 06:00 [pubmed]
PHST- 2014/08/27 06:00 [medline]
PHST- 2014/04/26 00:00 [pmc-release]
AID - 1756-9966-33-36 [pii]
AID - 10.1186/1756-9966-33-36 [doi]
PST - epublish
SO  - J Exp Clin Cancer Res. 2014 Apr 26;33(1):36. doi: 10.1186/1756-9966-33-36.