NF-¦ÊB signaling is activated and confers resistance to apoptosis in three-dimensionally cultured EGFR-mutant lung adenocarcinoma cells

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• 作者：Yuji Sakuma ; Yukiko Yamazaki ; Yoshiyasu Nakamura ; Mitsuyo Yoshihara ; Shoichi Matsukuma ; Shiro Koizume ; Yohei Miyagi
• 关键词：Lung adenocarcinoma ; EGFR mutation ; Three-dimensional culture ; NF-¦ÊB ; Apoptosis
• 刊名：Biochemical and Biophysical Research Communications
• 出版年：2012
• 出版时间：13 July, 2012
• 年：2012
• 卷：423
• 期：4
• 页码：667-671
• 全文大小：705 K

文摘

Epidermal growth factor receptor (EGFR)-mutant lung adenocarcinoma cells in suspension undergo apoptosis to a greater extent than adherent cells in a monolayer when EGFR autophosphorylation is inhibited by EGFR tyrosine kinase inhibitors (TKIs). This suggests that cell adhesion to a culture dish may activate an anti-apoptotic signaling pathway other than the EGFR pathway. Since the microenvironment of cells cultured in a monolayer are substantially different to that of cells existing in three-dimension (3D) in vivo, we assessed whether two EGFR-mutant lung adenocarcinoma cell lines, HCC827 and H1975, were more resistant to EGFR TKI-induced apoptosis when cultured in a 3D extracellular matrix (ECM) as compared with in suspension. The ECM-adherent EGFR-mutant cells in 3D were significantly less sensitive to treatment with WZ4002, an EGFR TKI, than the suspended cells. Further, a marked degradation of I¦ÊB¦Á, the inhibitor of nuclear factor (NF)-¦ÊB, was observed only in the 3D-cultured cells, leading to an increase in the activation of NF-¦ÊB. Moreover, the inhibition of NF-¦ÊB with pharmacological inhibitors enhanced EGFR TKI-induced apoptosis in 3D-cultured EGFR-mutant cells. These results suggest that inhibition of NF-¦ÊB signaling would render ECM-adherent EGFR-mutant lung adenocarcinoma cells in vivo more susceptible to EGFR TKI-induced cell death.