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Acquired tumor cell resistance to sunitinib by increased invasion and epithelial-mesenchymal transition in LL/2 murine lung cancer
OBJECTIVE: This study aims to investigate biological behavior changes in a murine lung cancer cell characterized by acquired resistance to sunitinib, a potent inhibitor of multiple-targeted receptor tyrosine kinase. METHODS: A lung cancer cell line resistant to sunitinib (LL/2-R) was developed from...
Autores principales: | , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Impact Journals LLC
2017
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5620255/ https://www.ncbi.nlm.nih.gov/pubmed/28978115 http://dx.doi.org/10.18632/oncotarget.19295 |
Sumario: | OBJECTIVE: This study aims to investigate biological behavior changes in a murine lung cancer cell characterized by acquired resistance to sunitinib, a potent inhibitor of multiple-targeted receptor tyrosine kinase. METHODS: A lung cancer cell line resistant to sunitinib (LL/2-R) was developed from its parental cell line (LL/2-P). Differences in biological characteristics and associated molecular profiles between these two cells were compared in vitro and in vivo. RESULTS: LL/2-R cells showed an approximately 5-fold higher IC(50) of sunitinib than LL/2-P cells and exhibited a reduced growth inhibition following sunitinib treatment compared with LL/2-P. In LL/2-R cells and tumors, increased migration, invasion and metastasis were observed, along with upregulation of MMP-2 and MMP-9. We also analyzed the molecular profiles involved in EMT, and found that E-cadherin was downregulated in LL/2-R tumors, and vimentin was upregulated in LL/2-R cells and tumors, along with β-catenin translocating to the nuclei in LL/2-R cells. Furthermore, transcriptional factors mediated EMT, snail and twist, and the secretion of TGFβ1 also increased in LL/2-R cells and tumors. CONCLUSIONS: We established a sunitinib-resistant lung cancer cell line and confirmed its drug-resistance to sunitinib in vivo. Our results implied that increased invasion and EMT may associate with the acquisition of resistant phenotype to sunitinib in cancer cells. |
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