Genome-wide gene expression analysis of chemoresistant pulmonary carcinoid cells

Abstract

Purpose: Carcinoids are highly chemoresistant tumors associated with a dismal prognosis. This study involved a comparison of the genome-wide gene expression pattern of a chemoresistant and a chemosensitive pulmonary carcinoid cell line to reveal factors that contribute to the resistant phenotype. Materials and methods: Gene expression of UMC-11 chemoresistant carcinoid cells as assessed by 32 K microarray was compared with H835 chemosensitive carcinoid cells, and the genes that were differentially expressed and expected to be related to chemoresistance were selected. Results: Drug-resistant UMC-11 cells exhibited increased expression of transcripts known to confer resistance to different cytostatics such as P-glycoprotein, multidrug resistance-associated proteins 2 and 3, effectors of the glutathione detoxification and xenobiotics degradation pathways, and ion transporters including Na + /K + -adenosine triphosphatase. In addition, enhanced t ranscription of several S100 proteins, capable of suppressing apoptosis, regulation of topoisomerase I (topo I) expression by antisense transcripts from TOPO1 pseudogenes, and alterations of the cytoskeleton seem to contribute to the multidrug-resistant phenotype. A multitude of epidermal growth factor (EGF)-related and neuropeptide growth factors, overexpression of proteases, and appearance of aerobic glycolytic metabolism complement the malignant phenotype of the UMC-11 cells. Conclusion:The multidrug-resistant phenotype of the UMC-11 pulmonary carcinoid cell line seems to be mediated by classical efflux pumps, drug metabolization or conjugation systems, and, possibly, modulation of apoptotic cell death by S100 proteins and topo I expression by pseudogene transcripts. Autocrine or paracrine stimulation by a host of EGF-related and neuropeptide growth factors, as well as high metastatic potency indicated by increased expression of components of aerobic glycolysis and proteolytic enzymes, may furthermore account for the failure of therapeutic interventions.

Exploring the multifaceted antitumor activity of axitinib in lung carcinoids

“…These three different cell lines are representative of well-differentiated pulmonary NETs, classified as typical LCs. Among these three cell lines, the responses to pharmacological treatments can vary significantly, reflecting the heterogeneity reported in this tumor and making them useful for comparative studies ( 26 – 28 ). In brief, cells were routinely seeded in T75 flasks containing RPMI medium (EuroClone™, Milan, Italy) and supplemented with 10% heat-activated fetal bovine serum (FBS) (EuroClone™, Milan, Italy) and 10 5 U·L−1 penicillin/streptomycin (EuroClone™, Milan, Italy).…”