Acquired tumor cell resistance to sunitinib by increased invasion and epithelial-mesenchymal transition in LL/2 murine lung cancer

Abstract

ObjectiveThis 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.MethodsA 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.ResultsLL/2-R cells showed an approximately 5-fold higher IC50 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.ConclusionsWe 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.

Long Non-coding RNA CCAT1 Acts as an Oncogene and Promotes Sunitinib Resistance in Renal Cell Carcinoma

“…According to the previous study ( 17 ), we established sunitinib-resistant sublines of ACHN and 786-O cells, named ACHN-SR and 786-O-SR, respectively. The half-maximal inhibitory concentration (IC 50 ) for the resistant cells and the corresponding parental cells was determined by MTT assay.…”

The multifaceted roles of matrix metalloproteinases in lung cancer

“…In gefitinib-resistant NSCLC cells, MMP-12 was inhibited through suppression of the EGFR/ERK signaling pathway, thus inhibited cell proliferation, invasion, and migration ( 48 ). In sunitinib-resistant LC cells, upregulation of MMP-2/9 contributed to cell migration, invasion and metastasis ( 49 ). In the crizotinib-resistant A549 cells, increased expression of MMP-9 induced EMT, enhanced cell invasion and migration ( 50 ).…”

Iron alters Ca2+ homeostasis in doxorubicin‐resistant K562 cells

“…One of the main mechanisms of drug resistance in cancer is the activation of a system of ATP‐dependent transporters, which increases the transmembrane efflux of drugs from cells, which decreases their concentration in the cytoplasm 2,3 . Drug target alterations, increased activity of cellular detoxifications, drug efflux, cell death inhibitions, alkaline shift of cellular pH, increased DNA damage repair, epithelial to mesenchymal transition (EMT), and increased pro‐survival signalling are of importance in the development of drug resistance mechanisms 4‐8 …”

“…2,3 Drug target alterations, increased activity of cellular detoxifications, drug efflux, cell death inhibitions, alkaline shift of cellular pH, increased DNA damage repair, epithelial to mesenchymal transition (EMT), and increased pro-survival signalling are of importance in the development of drug resistance mechanisms. [4][5][6][7][8] Iron and calcium are the fundamental elements in carrying out the vital functions of the cells. Calcium ion (Ca 2+ ) is referred to as a universal signalling molecule, and is known to regulate many aspects of cellular function including cell proliferation, differentiation, and apoptosis.…”