Gefitinib induces apoptosis in Caco-2 cells via ER stress-mediated mitochondrial pathways and the IRE1α/JNK/p38 MAPK signaling axis.

Abstract

Gefitinib, a selective EGFR-tyrosine kinase inhibitor, exhibits potent cytotoxic effects on colorectal cancer cells, though its precise mechanisms are not fully understood. In this study, we demonstrated that gefitinib induces a dose-dependent cytotoxic response in Caco-2 cells, characterized by disrupted microtubule networks, impaired migration, and reduced viability. Gefitinib triggered apoptosis, as indicated by increased levels of cleaved caspase-3, PARP, and elevated late apoptosis rates. Mechanistically, gefitinib-induced endoplasmic reticulum (ER) stress, marked by the upregulation of IRE1α, CHOP, and ATF4. ER stress inhibition by 4-PBA significantly reduced apoptosis and restored mitochondrial membrane potential (MMP). Additionally, gefitinib-induced apoptosis was mediated through the mitochondrial pathway, reflected by the modulation of Bcl-2 family proteins, including the upregulation of Bax and Bim. Inhibition of the IRE1α-mediated JNK/p38 MAPK pathway further mitigated gefitinib-induced apoptosis and restored MMP. These findings highlight the critical role of ER stress and the IRE1α-JNK/p38 MAPK axis in gefitinib-induced mitochondrial apoptosis, offering potential therapeutic targets for colorectal cancer.