DGG-100629 inhibits lung cancer growth by suppressing the NFATc1/DDIAS/STAT3 pathway

摘要

DNA damage-induced apoptosis suppressor (DDIAS) promotes the progression of lung cancer and hepatocellular carcinoma through the regulation of multiple pathways. We screened a chemical library for anticancer agent(s) capable of inhibiting DDIAS transcription. DGG-100629 was found to suppress lung cancer cell growth through the inhibition of DDIAS expression. DGG-100629 induced c-Jun NH(2)-terminal kinase (JNK) activation and inhibited NFATc1 nuclear translocation. Treatment with SP600125 (a JNK inhibitor) or knockdown of JNK1 restored DDIAS expression and reversed DGG-100629-induced cell death. In addition, DGG-100629 suppressed the signal transducer and activator of transcription (STAT3) signaling pathway. DDIAS or STAT3 overexpression restored lung cancer cell growth in the presence of DGG-100629. In a xenograft assay, DGG-100629 inhibited tumor growth by reducing the level of phosphorylated STAT3 and the expression of STAT3 target genes. Moreover, DGG-100629 inhibited the growth of lung cancer patient-derived gefitinib-resistant cells expressing NFATc1 and DDIAS. Our findings emphasize the potential of DDIAS blockade as a therapeutic approach and suggest a novel strategy for the treatment of gefitinib-resistant lung cancer. Lung cancer: Treating tumors resistant to standard therapy A drug targeting a protein implicated in cancer cell survival could offer a new way of treating lung tumors that are resistant to standard therapy. A South Korean team led by Misun Won, Korea Research Institute of Bioscience & Biotechnology, Daejeon, and Young-Dae Gong, Dongguk University, Seoul, screened a library of 1,500 chemicals looking for compounds that suppressed the activity of DDIAS, a protein preventing programmed cell death. Their search yielded a molecule that blocked a transcription factor from entering the nucleus and inducing the expression of DDIAS. In mice with implanted lung tumors, treatment with this molecule inhibited cancer growth and blocked downstream signaling of DDIAS. It also blunted the proliferation of cancer cells taken from patients who were resistant to gefitinib, a targeted drug therapy often used to treat lung tumors.