Abstract
Many studies are based on the hypothesis that recurrence and drug resistance in lung carcinoma are due to a subpopulation of cancer stem-like cells (CSLCs) in solid tumors. Therefore it is crucial to screen for and recognize lung CSLCs. In this study, we stimulated non-small cell lung cancer (NSCLC) A549 cells to display stem cell-like characteristics using a combination of five small molecule compounds. The putative A549 stem cells activated an important CSLC marker, CD133 protein, as well multiple CSLC-related genes including ATP-binding cassette transporter G2 (ABCG2), C-X-C chemokine receptor type 4 (CXCR4), NESTIN, and BMI1. The A549 stem-like cells displayed resistance to the chemotherapeutic drugs etoposide and cisplatin, epithelial-to-mesenchymal transition properties, and increased protein expression levels of NOTCH1 and Hes Family bHLH Transcription Factor 1 (HES1). When A549 cells were pretreated with a NOTCH signaling pathway inhibitor before compound induction, expression of the NOTCH1 target gene HES1 was reduced. This demonstrated that the NOTCH signaling pathway in the putative A549 stem-like cells had been activated. Together, the results of our study showed that a combination of five small molecule agents could transform A549 cells into putative stem-like cells, and that these compounds could also elevate CD133 and ABCG2 protein expression levels in H460 cells. This study provides a convenient method for obtaining lung CSLCs, which may be an effective strategy for developing lung carcinoma treatments.
Highlights
Lung cancer is one of the most common malignant carcinomas, with a poor 5-year survival rate of about 15% [1]
The growth of the remaining A549 cells did not exhibit apoptosis when treated with the small molecule agents, more apoptosis would have been observed if the treatment time was extended
We used five small molecule chemical compounds (VPA sodium salt, CHIR99021, E-616452, tranylcypromine and Deazaneplanocin A (DZnep)) in combination to stimulate A549 cells so they would exhibit putative stem-like cell properties
Summary
Lung cancer is one of the most common malignant carcinomas, with a poor 5-year survival rate of about 15% [1]. Non-small cell lung cancer (NSCLC) accounts for approximately 80% of all lung carcinomas and has high mortality due to tumor growth, recurrence, and drug resistance. Many studies have found that a subpopulation of lung cancer cells called cancer stem-like cells (CSLCs) are correlated with recurrence and drug resistance, which has led to a cancer stem cell hypothesis [2, 3]. It is crucial to identify and isolate them in solid tumors to potentially improve www.impactjournals.com/oncotarget cancer treatments and provide important predictive and prognostic information for lung cancer patients. Since only a small number of CSLCs exist in each tumor, identifying and isolating them have proven challenging
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