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

Joo Young Im, Bo Kyung Kim, Sung Hoon Yoon, Byoung Chul Cho, Yu Mi Baek, Mi Jung Kang, Nayeon Kim, Young Dae Gong, Misun Won

Research output: Contribution to journalArticlepeer-review

Abstract

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.

Original languageEnglish
Pages (from-to)643-653
Number of pages11
JournalExperimental and Molecular Medicine
Volume53
Issue number4
DOIs
Publication statusPublished - 2021 Apr

Bibliographical note

Funding Information:
This work was supported by the KRIBB Initiative Program (KGM4751713) and National Research Foundation (NRF) (NRF-2015M3A9A8032460, NRF-2017R1A2B2011936, NRF-2017M3A9F9030565).

Publisher Copyright:
© 2021, The Author(s).

All Science Journal Classification (ASJC) codes

  • Biochemistry
  • Molecular Medicine
  • Molecular Biology
  • Clinical Biochemistry

Fingerprint Dive into the research topics of 'DGG-100629 inhibits lung cancer growth by suppressing the NFATc1/DDIAS/STAT3 pathway'. Together they form a unique fingerprint.

Cite this