scholarly journals The IκB Kinase Inhibitor ACHP Targets the STAT3 Signaling Pathway in Human Non-Small Cell Lung Carcinoma Cells

Biomolecules ◽  
2019 ◽  
Vol 9 (12) ◽  
pp. 875 ◽  
Author(s):  
Jong Hyun Lee ◽  
Chakrabhavi Dhananjaya Mohan ◽  
Salundi Basappa ◽  
Shobith Rangappa ◽  
Arunachalam Chinnathambi ◽  
...  
Keyword(s):  
Signaling Pathway ◽  
Cell Lines ◽  
Inhibitory Activity ◽  
Small Cell ◽  
Nsclc Cell ◽  
Small Cell Lung ◽  
Cell Lung Carcinoma ◽  
Stat3 Signaling ◽  
Stat3 Signaling Pathway ◽  
Wide Range

STAT3 is an oncogenic transcription factor that regulates the expression of genes which are involved in malignant transformation. Aberrant activation of STAT3 has been observed in a wide range of human malignancies and its role in negative prognosis is well-documented. In this report, we performed high-throughput virtual screening in search of STAT3 signaling inhibitors using a cheminformatics platform and identified 2-Amino-6-[2-(Cyclopropylmethoxy)-6-Hydroxyphenyl]-4-Piperidin-4-yl Nicotinonitrile (ACHP) as the inhibitor of the STAT3 signaling pathway. The predicted hit was evaluated in non-small cell lung cancer (NSCLC) cell lines for its STAT3 inhibitory activity. In vitro experiments suggested that ACHP decreased the cell viability and inhibited the phosphorylation of STAT3 on Tyr705 of NSCLC cells. In addition, ACHP imparted inhibitory activity on the constitutive activation of upstream protein tyrosine kinases, including JAK1, JAK2, and Src. ACHP decreased the nuclear translocation of STAT3 and downregulated its DNA binding ability. Apoptosis was evidenced by cleavage of caspase-3 and PARP with the subsequent decline in antiapoptotic proteins, including Bcl-2, Bcl-xl, and survivin. Overall, we report that ACHP can act as a potent STAT3 signaling inhibitor in NSCLC cell lines.

scholarly journals Hypoxia-induced Tie1 Drives Stemness and Cisplatin Resistance in Non-small Cell Lung Carcinoma Cells

2020 ◽  
Author(s):  
Chaojie Li ◽  
Nannan Yang ◽  
Zhijin Chen ◽  
Ning Xia ◽  
Qungang Shan ◽  
...  
Keyword(s):  
Cell Lines ◽  
Lung Carcinoma ◽  
Cisplatin Resistance ◽  
Small Cell Lung Carcinoma ◽  
Small Cell ◽  
Nsclc Cell ◽  
Luciferase Reporter ◽  
Small Cell Lung ◽  
Cell Lung Carcinoma

Abstract Background: Drug resistance and metastasis involving hypoxic tumor environment and persistent stem cell populations are detrimental to the survival of patients with non-small cell lung carcinoma (NSCLC). Tie1 is upregulated in hypoxia and is believed to counteract the effectiveness of platinum agents, by promoting the stemness properties in cells. We have investigated the association of Tie1 with HIF-1α and cisplatin resistance in NSCLC cell lines. Methods: Expression of Tie1 in a pulmonary microvascular endothelial cell line (HPMEC) and in NSCLC cell lines was detected using qRT-PCR and western blot. The effect of Tie1 on cell stemness and migration was examined by sphere-forming assay and transwell assay in NSCLC cells with Tie1 silenced. The regulation of Tie1 by HIF-1α was evaluated by a dual-luciferase reporter assay and chromatinImmune precipitation (ChIP) analysis.Results: We found that hypoxia could induce stemness and cisplatin resistance in vitro. Tie1 was expressed at low levels in NSCLC cells when compared with human pulmonary microvascular endothelial cells, however, its expression was increased by hypoxia. Additionally, Tie1 knockdown could reduce the stemness properties and increase sensitivity to cisplatin in vitro and in a xenograft mouse model. The promoter of Tie1 contains two predicted hypoxia-response elements (HREs). We mutated both HRE sites and conducted chromatin immune-precipitation and promoter luciferase reporter assays and were able to conclude that the induction of Tie1 by hypoxia was HIF-1α-dependent. Conclusions: Our findings indicated that Tie1 is upregulated in a hypoxic environment by HIF-1α and contributes to tumorigenesis and cisplatin resistance through the promotion of stemness in NSCLC cells.

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