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

Zheng, Fang; Wu, Jingjing; Zhao, Shunyu; Luo, Qingmei; Tang, Qing; Yang, Lijun; Li, Liuning; Wu, Wanying; Hann, Swei Sunny

doi:10.1186/s13046-015-0160-7

Cited by 48 publications

(37 citation statements)

References 47 publications

(60 reference statements)

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“…Paradoxically, with the discoveries reported by Nevadunsky et al (13) and Lee et al (14), found that RUNX3 took on a growth-stimulating role, which was highly active in ovarian cancer cells, likewise, it even played an oncogenic role in basal cell carcinoma, head and neck squamous cell carcinoma (15,16). Moreover, reports have found that RUNX3 inactivation can be correlated with advanced tumor stage and negative prognosis (17), and acts as a crucial early step in the development of tumors (18,19). To date, our purpose is to preliminarily explore the expression and the biological behavior of RUNX3 in cervical cancer.…”

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confidence: 98%

The roles of RUNX3 in cervical cancer cells inï¿½vitro

Fan

Deng

et al. 2018

Oncol Lett

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Abstract. RUNX3 serves an important role in development of various types of human cancer. The purpose of the present study was to investigate the potential biological function of RUNX3 in cervical cancer cells. In the present study, a RUNX3 overexpressed model was constructed in Hec1 cells by PCDNA3.1-RUNX3 transfection. Western blot analysis was used to measure RUNX3 expression in cervical cancer cells. Immunofluorescence analysis was performed to examine subcellular localization of RUNX3 in cervical cancer cells. Effects of RUNX3 expression on proliferation, migration and invasion of cervical cancer cells were detected by colony formation assay, wound healing assay and Transwell assay, respectively. Immunofluorescence confirmed the nuclear location of RUNX3 in cervical cancer cell. Result sindicated that upregulation of RUNX3 expression inhibited proliferation, migration and invasion of cervical cancer cells. However, knockdown of RUNX3 expression promoted the proliferation, migration and invasion of cervical cancer cells. Hence, RUNX3 may serve as a tumor suppressor gene in cervical cancer. IntroductionCervical cancer is one of the most common malignancies in women. The incidence is second only to that of breast cancer, which also poses a serious threat to women's health (1). In recent years, one study found that the continuous upgrading of screening methods and the popularity of the human papillomavirus vaccine had caused the incidence of both cervical cancer cases and mortality to decline. Due to the uneven distribution of resources, the incidence is still rising in developing countries, and the trend may affect younger patients (2). As molecular biology research becomes more sophisticated, more and more genes have been found to be involved in the development of cervical cancer. Finding new molecular targets for the prevention and treatment of cervical cancer could have far-reaching implications.The RUNX3 tumor suppressor gene was discovered a few years ago. With RUNX1 and RUNX2, it makes up the transcription factor RUNX family (3). RUNX1 is associated with hematopoietic function (4), and RUNX2 is an important bone formation regulator (5). RUNX3 is located on chromosome 1p36.1 and contains a p1 promoter and p2 promoter (6). Alkaline phosphatase (ALP), a marker of BMP9-induced late osteogenic differentiation was enhanced by the overexpression of RUNX3, whereas it was inhibited by the knockdown of RUNX3 (7). It was first reported to be a tumor suppressor gene in gastric epithelial cells (8), and it was also reported to absent or mutated in a variety of cancers for hemizygous deletions (9), protein mislocalization, epigenetic alterations (10), and histone modifications (11). Suzuki et al (12), initially described the DNA promoter of RUNX3 hypermethylation as a characteristic of breast cancer. Paradoxically, with the discoveries reported by Nevadunsky et al (13) and Lee et al (14), found that RUNX3 took on a growth-stimulating role, which was highly active in ovarian cancer cells, likewise, it even played an o...

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confidence: 98%

The roles of RUNX3 in cervical cancer cells inï¿½vitro

Fan

Deng

et al. 2018

Oncol Lett

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“…Treatment with baicalein also inhibited lung carcinogenesis by counteracting lysosomal and microsomal abnormalities through the reduction of oxidative damages and downregulation of CYP1A1 [95]. Moreover, baicalein treatment inhibited proliferation and induced apoptosis of NSC lung cancer cells by phosphorylation of AMPKα and MEK/ERK1/2, and upregulating the expression of RUNX3 and FOXO3a [96]. Interestingly, baicalein effectively decreased the levels of TNF-α, IL-β, iNOS, COX-2, MMP-2, and MMP-9.…”

Section: Baicalein and Lung Cancermentioning

confidence: 99%

The Fascinating Effects of Baicalein on Cancer: A Review

Liu

Dong

Gao

et al. 2016

IJMS

189

133

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Cancer is one of the leading causes of death worldwide and a major global health problem. In recent decades, the rates of both mortality and morbidity of cancer have rapidly increased for a variety of reasons. Despite treatment options, there are serious side effects associated with chemotherapy drugs and multiple forms of drug resistance that significantly reduce their effects. There is an accumulating amount of evidence on the pharmacological activities of baicalein (e.g., anti-inflammatory, antioxidant, antiviral, and antitumor effects). Furthermore, there has been great progress in elucidating the target mechanisms and signaling pathways of baicalein’s anti-cancer potential. The anti-tumor functions of baicalein are mainly due to its capacities to inhibit complexes of cyclins to regulate the cell cycle, to scavenge oxidative radicals, to attenuate mitogen activated protein kinase (MAPK), protein kinase B (Akt) or mammalian target of rapamycin (mTOR) activities, to induce apoptosis by activating caspase-9/-3 and to inhibit tumorinvasion and metastasis by reducing the expression of matrix metalloproteinase-2/-9 (MMP-2/-9). In this review, we focused on the relevant biological mechanisms of baicalein involved in inhibiting various cancers, such as bladder cancer, breast cancer, and ovarian cancer. Moreover, we also summarized the specific mechanisms by which baicalein inhibited the growth of various tumors in vivo. Taken together, baicalein may be developed as a potential, novel anticancer drug to treat tumors.

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“…Numerous studies have demonstrated that FOXO3a regulated a wide range of biological functions including growth, differentiation, apoptosis, protection against oxidative stress, and metabolism [9-11]. Exogenously expression of FOXO3a has been shown to inhibit tumor growth in several cancer types [12, 13]. These observations suggest that FOXO3a functions as a tumor suppressor and may serve as a therapeutic target for the cancer treatment.…”

Section: Introductionmentioning

confidence: 99%

Combination of Solamargine and Metformin Strengthens IGFBP1 Gene Expression Through Inactivation of Stat3 and Reciprocal Interaction Between FOXO3a and SP1

Tang

Zheng

et al. 2017

Cell Physiol Biochem

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Background/Aims: Solamargine, one natural photochemical component from traditional plants, has been shown to have anti-cancers properties. We previously showed that solamargine inhibited the growth of non-small-cell lung cancer (NSCLC) cells through suppression of prostaglandin E2 (PGE₂) receptor EP4 gene and regulation of downstream signaling pathways. However, the detailed mechanism underlying this, especially in combination of metformin, a known AMPK activator, still remained to be determined. Methods: Cell viability was measured using a 3-(4, 5-dimethylthiazol-2-yl)-2, 5-diphenyltetrazolium bromide (MTT) and colorimetric 5-bromo-2-deoxyuridine (BrdU) ELISA methods, respectively. Western blot analysis and immunohistochemistry were performed to examine the phosphorylation and protein expressions of signal transducer and activator of transcription 3 (Stat3), SP1, forkhead box O3a (FOXO3a), and insulin-like growth factor (IGF)-IGF binding protein 1 (IGFBP1). The expression of IGFBP1 mRNA was measured by quantitative real time PCR (qRT-PCR). Silencing of FOXO3a and IGFBP1 were examined by siRNA procedures. Exogenously expression of SP1, FOXO3a, and IGFBP1 were carried out by transient transfection assays. The promoter activity of IGFBP1 was tested using Secrete-Pair^TM Dual Luminescence Assay Kit. A xenografted tumor model was used to further test the effect of solamargine in combining with metformin in vivo. Results: We further demonstrated that solamargine inhibited growth and induced cell cycle arrest in other NSCLC cell lines. Through mechanism-based approaches, we showed that solamargine decreased the phosphorylation of Stat3; In addition, solamargine induced FOXO3a, whereas reduced SP1 protein levels; all of which were abrogated in cells with overexpressed Stat3 gene. Interestingly, there is interaction between FOXO3a and SP1. Moreover, solamargine increased mRNA, protein expression and promoter activity of IGFBP1, which was not observed in cells with overexpressed SP1 or with silenced FOXO3a genes. Finally, ablation of IGFBP1 expression by siRNA blocked the effect of solamargine on cell growth inhibition. More importantly, there was a synergy of combination of solamargine and metformin. Similar findings were also observed in vivo. Conclusion: Our results show that solamargine increases IGFBP1 gene expression through inactivation of Stat3, followed by regulation and reciprocal interaction of FOXO3a and SP1 in vitro and in vivo. This ultimately leads to suppression of human lung cancer cell growth. Moreover, this is a synergy of solamargine in combination with metformin in this process. This study unravels a novel mechanism underlying the anti-lung cancer effects of solamargine in combination of metformin, and suggests a potential new lung cancer associated therapy.

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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

Cited by 48 publications

References 47 publications

The roles of RUNX3 in cervical cancer cells inï¿½vitro

The roles of RUNX3 in cervical cancer cells inï¿½vitro

The Fascinating Effects of Baicalein on Cancer: A Review

Combination of Solamargine and Metformin Strengthens IGFBP1 Gene Expression Through Inactivation of Stat3 and Reciprocal Interaction Between FOXO3a and SP1

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