PT  - JOURNAL ARTICLE
AU  - HYUN-KYUNG LEE
AU  - MIN HYE NOH
AU  - SEUNG-WOO HONG
AU  - SEUNG-MI KIM
AU  - SUNG HYUN KIM
AU  - YEONG SEOK KIM
AU  - V. COURTNEY BROADDUS
AU  - DAE YOUNG HUR
TI  - Erlotinib Activates Different Cell Death Pathways in EGFR-mutant Lung Cancer Cells Grown in 3D <em>Versus</em> 2D Culture Systems
AID  - 10.21873/anticanres.14883
DP  - 2021 Mar 01
TA  - Anticancer Research
PG  - 1261--1269
VI  - 41
IP  - 3
4099  - http://ar.iiarjournals.org/content/41/3/1261.short
4100  - http://ar.iiarjournals.org/content/41/3/1261.full
SO  - Anticancer Res2021 Mar 01; 41
AB  - Background/Aim: Non-small cell lung cancer patients with epidermal growth factor receptor (EGFR) mutation have been shown to have a good response to erlotinib, a receptor tyrosine kinase inhibitor of EGFR. In this study, we found that the cell death pathways activated by erlotinib in 2D and 3D culture systems are different. Materials and Methods: The cell death pathways induced by erlotinib were evaluated by flow cytometry and immunoblotting in both 2D and 3D culture systems of EGFR mutant lung cancer cells. Results: Treatment with erlotinib induced caspase 8 activation and up-regulation of TNF-related apoptosis-inducing ligand (TRAIL) expression only in 3D cultures. Knockdown of TRAIL attenuated both erlotinib-induced activation of caspase-8 and apoptosis in 3D cultures. Erlotinib also increased LC3, an autophagy marker, expression and c-Jun N terminal kinase (JNK) activation. Both 3-MA as an autophagy inhibitor and SP600125 as a JNK inhibitor, significantly inhibited erlotinib-induced cell death. Conclusion: Erlotinib induces apoptotic cell death in 3D cultures through an autophagy-TRAIL-JNK pathway.