BIM induction of apoptosis triggered by EGFR-sensitive and resistance cell lines of non-small-cell lung cancer.
We sought to improve the understanding of oncogene-dependent and independent non-small-cell lung cancer (NSCLC), which could provide insight into mechanism of sensitivity and/or resistance to tyrosine kinase inhibitors or chemotherapeutics. NSCLC cell lines with different EGFR genotypes were used in this study; MTT assay and flow cytometry were applied to study the sensitivities of these cell lines to gefitinib and cisplatin. Western blot was performed to determine the expression levels of BIM and other Bcl-2 family proteins pre- and pro-treatment. Gefitinib provoked apoptosis of caspase activation via the intrinsic pathways and significantly up-regulated expression of BIM protein in drug-sensitive PC-9 cell line, but not resistant PC-9/BB4 cell line. The knockdown of BIM expression by RNA interference virtually eliminated gefitinib-induced cell killing in PC-9 cells in vitro. Cisplatin could induce apoptosis of the cell lines, including H1299, A549, PC-9, and PC-9/BB4 cells, but which was not associated with overexpression of BIM. BIM is involved in TKI-induced apoptosis in sensitive EGFR-mutant cell line. Down-regulation of BIM and resistance to gefitinib were both seen in the acquired resistant PC-9/BB4 cell line. The induction of BIM may have a role in the treatment of TKI-resistant tumors.
Department of Oncology; Pulmonary Hospital, Tongji University School of Medicine, Yangpu Region, Shanghai, 200433, China.
Zhanxia
Z
Li
Songwen
S
Zhou
Ling
L
Zhang
Chunxia
C
Su
Jinqin
J
Hang
Yinmin
Y
Zhao
Bo
B
Su
Caicun
C
Zhou
D000970:Antineoplastic Agents / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects / Q000235:genetics*; D051017:Apoptosis Regulatory Proteins / Q000235:genetics* / Q000378:metabolism; D000072224:Bcl-2-Like Protein 11; D015153:Blotting, Western; D002289:Carcinoma, Non-Small-Cell Lung / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D045744:Cell Line, Tumor; D002469:Cell Separation; D002945:Cisplatin / Q000494:pharmacology; D019008:Drug Resistance, Neoplasm / Q000235:genetics*; D066246:ErbB Receptors / Q000235:genetics; D005434:Flow Cytometry; D000077156:Gefitinib; D006801:Humans; D008175:Lung Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D008565:Membrane Proteins / Q000235:genetics* / Q000378:metabolism; D009154:Mutation; D011518:Proto-Oncogene Proteins / Q000235:genetics* / Q000378:metabolism; D011799:Quinazolines / Q000494:pharmacology; D034622:RNA Interference; D034741:RNA, Small Interfering
D000970:Antineoplastic Agents; D051017:Apoptosis Regulatory Proteins; C000606775:BCL2L11 protein, human; D000072224:Bcl-2-Like Protein 11; D008565:Membrane Proteins; D011518:Proto-Oncogene Proteins; D011799:Quinazolines; D034741:RNA, Small Interfering; C512478:EGFR protein, human; D066246:ErbB Receptors; D002945:Cisplatin; D000077156:Gefitinib