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

Jong Hyun Lee,Salundi Basappa,Gautam Sethi,Shobith Rangappa,Arunachalam Chinnathambi,Chakrabhavi Dhananjaya Mohan,Sulaiman Ali Alharbi,Kwang Seok Ahn,Tahani Awad Alahmadi,Alan Prem Kumar,Kanchugarakoppal S Rangappa

doi:10.3390/biom9120875

Abstract

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.

Highlights

Lung cancer is the second most common type of cancer in both sexes and a leading cause of cancer-related deaths [1,2,3,4]
The results shown are representative of three independent experiments. *** p < 0.001. (F) A549 cells were treated as described above in panel C, and western blot was performed using various antibodies. −: Non-treatment, +: Amino-6-[2-(Cyclopropylmethoxy)-6-Hydroxyphenyl]-4-Piperidin-4-yl Nicotinonitrile (ACHP) treatment
The ranked compounds are provided as a supplementary file and the structure of the top four ranked compounds that target STAT3 are provided as a supplementary figure

Summary

Introduction

Lung cancer is the second most common type of cancer in both sexes and a leading cause of cancer-related deaths [1,2,3,4]. Non-small cell lung cancer (NSCLC) and small cell lung carcinoma are the two major subtypes, which account for about 80–85% and 10–15% of all lung cancer, respectively [5,6,7,8,9,10]. The development and progression of NSCLC are tightly associated with smoking, exposure to asbestos and radon, drinking of arsenic-contaminated water, family history, and inhalation of carcinogens, such as beryllium, mustard gas, cadmium, nickel, etc. Surgical approaches, such as segmentectomy, sleeve resection, lobectomy, pneumonectomy, and non-surgical approaches, including radiation therapy, chemotherapy, and immunotherapy, have been implemented as the treatment strategies in NSCLC [12,13]. Signal transducer and activator of transcription (STAT) is a family of cytoplasmic transcription factors comprising of seven variants (STAT1, STAT2, STAT3, STAT4, STAT5a, STAT5b, and STAT6)

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Results

Conclusion