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Baicalein Increases the Expression and Reciprocal Interplay of RUNX3

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Baicalein Increases the Expression and Reciprocal Interplay of RUNX3 Zheng et al. Journal of Experimental & Clinical Cancer Research (2015) 34:41 DOI 10.1186/s13046-015-0160-7 RESEARCH ARTICLE Open Access Baicalein increases the expression and reciprocal interplay of RUNX3 and FOXO3a through crosstalk of AMPKα and MEK/ERK1/2 signaling pathways in human non-small cell lung cancer cells Fang Zheng1, Jingjing Wu1, Shunyu Zhao1, Qingmei Luo1, Qing Tang1, LiJun Yang1, Liuning Li2, WanYing Wu2 and Swei Sunny Hann1,3* Abstract Background: Baicalein, a natural flavonoid obtained from the Scutellaria baicalensis root, has been reported to inhibit growth of human lung cancer. However, the detailed mechanism underlying this has not been well elucidated. Methods: Cell viability was measured using a 3-(4, 5-dimethylthiazol-2-yl)-2, 5-diphenyltetrazolium bromide (MTT) assays. Apoptosis was detected by flow cytometry analysis and caspase 3/7 assays. The expression of RUNX3 and FOXO3a mRNA were measured by real time RT-PCR methods. Western blot analysis was performed to measure the phosphorylation and protein expression of AMP-activated protein kinase alpha (AMPKα) and extracellular signal-regulated kinase 1/2 (ERK1/2), runt-related transcription factor 3 (RUNX3) and forkhead box O3a (FOXO3a). Silencing of FOXO3a and RUNX3 were performed by small interfering RNA (siRNA) methods. Exogenous expression of FOXO3a or RUNX3 was carried out by electroporated transfection assays. Results: We showed that baicalein significantly inhibited growth and induced apoptosis of non-small cell lung cancer (NSCLC) cells in a time- and dose-dependent manner. Baicalein induced RUNX3 and FOXO3a protein expression, and increased phosphorylation of AMPKα and ERK1/2. Moreover, the inhibitors of AMPK and MEK/ERK1/2 reversed the effect of baicalein on RUNX3 and FOXO3a protein expression. Interestingly, while compound C had little effect on blockade of baicalein-induced phosphorylation of ERK1/2, PD98059 significantly abrogated baicalein-induced phosphorylation of AMPKα. Intriguingly, while silencing of RUNX3 abolished the effect of baicalein on expression of FOXO3a and apoptosis, silencing of FOXO3a significantly attenuated baicalein-reduced cell proliferation. On the contrary, overexpression of FOXO3a restored the effect of baicalein on cell growth inhibition in cells silencing of endogenous FOXO3a gene and enhanced the effect of baicalein on RUNX3 protein expression. Finally, exogenous expression of RUNX3 increased FOXO3a protein and strengthened baicalein-induced phosphorylation of ERK1/2. (Continued on next page) * Correspondence: [email protected] 1Laboratory of Tumor Biology, Guangdong Provincial Hospital of Chinese Medicine, The Second Clinical Medical Collage, University of Guangzhou Traditional Chinese Medicine, Guangzhou, Guangdong Province 510120, China 3Higher Education Mega Center, No. 55, Neihuan West Road, Panyu District, Guangzhou, Guangdong Province 510006, People’s Republic of China Full list of author information is available at the end of the article © 2015 Zheng et al.; licensee BioMed Central. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly credited. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated. Zheng et al. Journal of Experimental & Clinical Cancer Research (2015) 34:41 Page 2 of 13 (Continued from previous page) Conclusion: Collectively, our results show that baicalein inhibits growth and induces apoptosis of NSCLC cells through AMPKα- and MEK/ERK1/2-mediated increase and interaction of FOXO3a and RUNX3 protein. The crosstalk between AMPKα and MEK/ERK1/2 signaling pathways, and the reciprocal interplay of FOXO3a and RUNX3 converge on the overall response of baicalein. This study reveals a novel mechanism for regulating FOXO3a and RUNX3 signaling axis in response to baicalein and suggests a new strategy for NSCLC associated targeted therapy. Keywords: Baicalein, NSCLC, RUNX3, FOXO3a, MEK/ERK1/2, AMPKα Introduction regulated expression of genes involved in apoptosis, cell Lung cancer remains one of the leading causes of cycle arrest, oxidative stress resistance and was nega- cancer-related death in men and women worldwide [1]. tively regulated by growth factors [15]. During tumor Non-small cell lung cancer (NSCLC) is more common development, inhibition of FOXO3a stimulated cell trans- and the majority of patients present with advanced stage formation, tumor progression, and angiogenesis [16]. On [2]. Emerging data demonstrate promising outcome of the contrary, overexpression of FOXO3a suppressed other non-surgical treatment in patients with advanced cancer cell growth, modulated expression of downstream lung cancer. Traditional Chinese medicine (TCM) plays effectors, induced apoptosis, and reduced tumor size an important role in protecting cancer patients against [17-19]. These results indicated a tumor suppressor role suffering from other treatment related complications, of FOXO3a, which could be a potential target for the helping in supportive and palliative care by reducing treatment of cancers. toxicity of conventional therapy and improving quality The runt-related transcription factors (RUNXs) belong of life [3-6]. However, the mechanisms by which TCM in to a family of conserved proteins, which share the highly improving the therapeutic efficiency against the lung homologous DNA-binding, N-terminal Runt domain malignancies remains poorly understood. [20]. To date, three RUNX transcription factors, i.e., Phytochemicals are naturally occurring, plant-based RUNX1, RUNX2 and RUNX3, have been identified. substances that have garnered attention for their anti- Among these, RUNX3, the smallest member of RUNX cancer properties, both as therapeutics and components family, reported to be involved in various cancer processes, of the diet for chemoprevention. One particularly such as cell growth, apoptosis, angiogenesis, and metastasis ubiquitous group of phytochemicals is the polyphenolic [21]. Study demonstrated that RUNX3 is a tumor suppres- flavonoids. Baicalein, a natural flavonoid obtained from sor gene, which is absent or mutated in several types of the Scutellaria baicalensis root, were showed to inhibit cancers including lung due to hemizygous deletions or proliferation of several malignant tumors including lung epigenetic alterations [22]. One report found that RUNX3 cancer [7-10]. One study showed that the therapeutic inactivation is a crucial early step in the development of effects of baicalein are attributed to control proliferation, lung malignancy [23]. metastasis and inflammatory microenvironment in In this study, we explore the potential mechanism by human lung cancer cells [7]. Multiple signaling pathways which baicalein controls lung cancer cell proliferation. and potential targets involved in the baicalein-suppressed cancer cell growth, including lung, have been reported in Materials and methods the past [7,9-11]. However, the underlying molecular Reagents mechanisms associated with its efficacy in targeting lung Monoclonal antibodies against to total ERK1/2, AMPKα cancer are largely unknown. and the phosphor-forms were purchased from Cell Mammalian forkhead members of the class O (FOXO) Signaling Technology Inc. (Beverly, MA, USA). The transcription factors, a superfamily of proteins are impli- FOXO3a and RUNX3 antibodies were obtained from cated in the regulation of variety of biological functions, Epitomics (Burlingame, CA, USA). PD98059 (MAPK such as apoptosis, cell cycle transitions, DNA repair, extracellular signaling-regulated kinase (ERK) kinase metabolism, oxidative stress, and cell differentiation (MEK)/ERK1/2 inhibitor) and compound C (inhibitor of [12]. In humans, four members of the FOXO transcrip- AMPK) were purchased from Merck Millipore (Billerica, tion factors (FOXO1, FOXO3a, FOXO4 and FOXO6) MA, USA), MTT powder was purchased from Sigma have been found [13]; they share a high degree of Aldrich (St. Louis, MO, USA). FOXO3a and RUNX3 small conserved 100-residue DNA-binding domain, so-called interfering RNAs (siRNAs) were obtained from Santa Cruz forkhead domain in their DNA-binding area [14]. Biotechnology, Inc. (Santa Cruz, CA, USA). Baicalein was Among them, FOXO3a has been extensively studied as a purchased from Chengdu Must Bio-technology Company crucial protein. Previous studies showed that FOXO3a (Chengdu, Sichuan, China). The drugs were freshly diluted Zheng et al. Journal of Experimental & Clinical Cancer Research (2015) 34:41 Page 3 of 13 to the final concentration with culture medium before NSCLC cells were seeded in 96-well plates and treated applying to experiments. with or without baicalein for 48 h. Afterwards, the cells were lysed and incubated with 100 μL of Apo-ONE Cell lines and cultures Caspase-3/7 reagent (substrate and buffer in the ratio Human lung adenocarcinoma cells (PC9, H1299, H1650, of 1:100). After 1 h incubation in the dark at RT, the A549, H358 and H1975) were obtained from the fluorescence of each well was measured at 485–520 nm by Chinese Academy of Sciences Cell Bank of Type Culture reading in an Epoch microplate reader (Biotek Instruments; Collection (Shanghai, China) and the Cell Line Bank at the Winooski, VT, USA). Laboratory Animal Center of Sun Yat-sen University (Guangzhou, China). The cells
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