RT Journal Article
SR Electronic
T1 Macrophage-induced Expression of TonEBP/NFAT5 Is Associated With Gefitinib Resistance and Migration in PC-9 Cells
JF Anticancer Research
JO Anticancer Res
FD International Institute of Anticancer Research
SP 3867
OP 3874
DO 10.21873/anticanres.17213
VO 44
IS 9
A1 SONG, HEE JU
A1 SHARMA, SUBODH
A1 KIM, TAEHEE
A1 KIM, YOUNG HWAN
A1 KIM, SOO JIN
A1 KANG, MIN WOONG
A1 LEE, SANG DO
YR 2024
UL http://ar.iiarjournals.org/content/44/9/3867.abstract
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.