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Ailanthone inhibits non-small cell lung cancer cell growth through repressing DNA replication via downregulating RPA1.

ABSTRACT: BACKGROUND:The identification of bioactive compounds from Chinese medicine plays a crucial role in the development of novel reagents against non-small lung cancer (NSCLC). METHODS:High throughput screening assay and analyses of cell growth, cell cycle, apoptosis, cDNA microarray, BrdU incorporation and gene expression were performed. RESULTS:Ailanthone (Aila) suppressed NSCLC cell growth and colony formation in vitro and inhibited NSCLC tumour growth in subcutaneously xenografted and orthotopic lung tumour models, leading to prolonged survival of tumour-bearing mice. Moreover, Aila induced cell cycle arrest in a dose-independent manner but did not induce apoptosis in all NSCLC cells. Furthermore, 1222 genes were differentially expressed upon Aila administration, which were involved in 21 signal pathways, such as DNA replication. In addition, Aila dose-dependently decreased BrdU incorporation and downregulated the expression of replication protein A1 (RPA1). CONCLUSIONS:Aila inhibited the growth of NSCLC cells through the repression of DNA replication via downregulating RPA1, rather than through cell cycle arrest and apoptosis. Our findings suggested that Aila could be used as a promising therapeutic candidate for NSCLC patients.

SUBMITTER: Ni Z

PROVIDER: S-EPMC5729430 | biostudies-literature | 2017 Nov

REPOSITORIES: biostudies-literature

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Ailanthone inhibits non-small cell lung cancer cell growth through repressing DNA replication via downregulating RPA1.

Ni Zhongya Z Yao Chao C Zhu Xiaowen X Gong Chenyuan C Xu Zihang Z Wang Lixin L Li Suyun S Zou Chunpu C Zhu Shiguo S

British journal of cancer 20171012 11

<h4>Background</h4>The identification of bioactive compounds from Chinese medicine plays a crucial role in the development of novel reagents against non-small lung cancer (NSCLC).<h4>Methods</h4>High throughput screening assay and analyses of cell growth, cell cycle, apoptosis, cDNA microarray, BrdU incorporation and gene expression were performed.<h4>Results</h4>Ailanthone (Aila) suppressed NSCLC cell growth and colony formation in vitro and inhibited NSCLC tumour growth in subcutaneously xenog ...[more]

PMID: 29024939

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Project description:BackgroundProgressive hepatitis B virus (HBV) infection can result in cirrhosis, hepatocellular cancer, and chronic hepatitis. While antiviral drugs that are now on the market are efficient in controlling HBV infection, finding a functional cure is still quite difficult. Identifying host factors involved in regulating the HBV life cycle will contribute to the development of new antiviral strategies. Zinc finger proteins have a significant function in HBV replication, according to earlier studies. Zinc finger protein 148 (ZNF148), a zinc finger transcription factor, regulates the expression of various genes by specifically binding to GC-rich sequences within promoter regions. The function of ZNF148 in HBV replication was investigated in this study.MethodsHepG2-Na+/taurocholate cotransporting polypeptide (HepG2-NTCP) cells and Huh7 cells were used to evaluate the function of ZNF148 in vitro. Northern blotting and real-time PCR were used to quantify the amount of viral RNA. Southern blotting and real-time PCR were used to quantify the amount of viral DNA. Viral protein levels were elevated, according to the Western blot results. Dual-luciferase reporter assays were used to examine the transcriptional activity of viral promoters. ZNF148's impact on HBV in vivo was investigated using an established rcccDNA mouse model.ResultsZNF148 overexpression significantly decreased the levels of HBV RNAs and HBV core DNA in HBV-infected HepG2-NTCP cells and Huh7 cells expressing prcccDNA. Silencing ZNF148 exhibited the opposite effects in both cell lines. Furthermore, ZNF148 inhibited the activity of HBV ENII/Cp and the transcriptional activity of cccDNA. Mechanistic studies revealed that ZNF148 attenuated retinoid X receptor alpha (RXRα) expression by binding to the RXRα promoter sequence. RXRα binding site mutation or RXRα overexpression abolished the suppressive effect of ZNF148 on HBV replication. The inhibitory effect of ZNF148 was also observed in the rcccDNA mouse model.ConclusionsZNF148 inhibited HBV replication by downregulating RXRα transcription. Our findings reveal that ZNF148 may be a new target for anti-HBV strategies.

Dataset Information

Ailanthone inhibits non-small cell lung cancer cell growth through repressing DNA replication via downregulating RPA1.

Publications

Ailanthone inhibits non-small cell lung cancer cell growth through repressing DNA replication via downregulating RPA1.

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