PT  - JOURNAL ARTICLE
AU  - SONG, HEE JU
AU  - SHARMA, SUBODH
AU  - KIM, TAEHEE
AU  - KIM, YOUNG HWAN
AU  - KIM, SOO JIN
AU  - KANG, MIN WOONG
AU  - LEE, SANG DO
TI  - Macrophage-induced Expression of TonEBP/NFAT5 Is Associated With Gefitinib Resistance and Migration in PC-9 Cells
AID  - 10.21873/anticanres.17213
DP  - 2024 Sep 01
TA  - Anticancer Research
PG  - 3867--3874
VI  - 44
IP  - 9
4099  - http://ar.iiarjournals.org/content/44/9/3867.short
4100  - http://ar.iiarjournals.org/content/44/9/3867.full
SO  - Anticancer Res2024 Sep 01; 44
AB  - Background/Aim: Macrophages prevail in the microenvironment of several tumors, including non-small-cell lung cancer (NSCLC), where they secrete pro-tumorigenic factors that contribute to cancer progression. This study investigated the role of macrophages on the resistance of epidermal growth factor receptor (EGFR)-mutated NSCLC cells to tyrosine kinase inhibitors (TKIs). Materials and Methods: EGFR-mutated cell lines PC-9 and HCC827 were cocultured with macrophages and treated with TKIs (erlotinib and gefitinib). The effects of the macrophage-conditioned medium (macrophage CM) on gefitinib resistance and cell migration were also evaluated. Results: Co-culture with macrophages significantly enhanced the resistance to erlotinib and gefitinib in PC-9 and HCC827 cells compared to that in cells cultured independently. Macrophage CM markedly induced gefitinib resistance in PC-9 cells, with maximum resistance observed at 50% CM concentration. This resistance persisted for up to 48 h post-CM removal. Macrophage CM inhibited gefitinib-induced apoptosis, as evidenced by the decreased expression of cleaved caspase-3, PARP, and BIM. Additionally, macrophage CM increased the migration ability of PC-9 cells, as shown by the wound healing and transwell migration assays. Studies have shown that TonEBP is crucial in cancer metastasis and drug resistance; we found that inhibition of TonEBP/NFAT5 expression reduced gefitinib resistance and migration in macrophage CM-induced PC-9 cells, indicating its role as mediator of these effects. Conclusion: Macrophages contribute to TKI resistance and enhance the migration of EGFR-mutated NSCLC cells through mechanisms involving TonEBP/NFAT5. Therefore, targeting TonEBP/NFAT5 represents a potential therapeutic strategy for overcoming macrophage-induced TKI resistance in NSCLC cells.