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KMID : 0620920210530040643
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Experimental & Molecular Medicine
2021 Volume.53 No. 4 p.643 ~ p.653
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DGG-100629 inhibits lung cancer growth by suppressing the NFATc1/DDIAS/STAT3 pathway
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Im Joo-Young
Kim Bo-Kyung
Yoon Sung-Hoon
Cho Byoung-Chul
Baek Yu-Mi
Kang Mi-Jung
Kim Na-Yeon
Gong Young-Dae
Won Mi-Sun
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Abstract
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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.
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KEYWORD
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Apoptosis, Drug development, Non-small-cell lung cancer, Reporter genes, Targeted therapies
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