BMP4 Upregulation Is Associated with Acquired Drug Resistance and Fatty Acid Metabolism in EGFR-Mutant Non-Small-Cell Lung Cancer Cells

Abstract

Lung cancer is the leading cause of cancer-associated deaths worldwide. In particular, non-small-cell lung cancer (NSCLC) cells harboring epidermal growth factor receptor (EGFR) mutations are associated with resistance development of EGFR tyrosine kinase inhibitor (EGFR-TKI) treatment. Recent findings suggest that bone morphogenetic proteins (BMPs) and microRNAs (miRNAs) might act as oncogenes or tumor suppressors in the tumor microenvironment. In this study, for the first time, we identified the potential roles of BMPs and miRNAs involved in EGFR-TKI resistance by analyzing datasets from a pair of parental cells and NSCLC cells with acquired EGFR-TKI resistance. BMP4 was observed to be significantly overexpressed in the EGFR-TKI-resistant cells, and its mechanism of action was strongly associated with the induction of cancer cell energy metabolism through the modulation of Acyl-CoA synthetase long-chain family member 4. In addition, miR-139-5p was observed to be significantly downregulated in the resistant NSCLC cells. The combination of miR-139-5p and yuanhuadine, a naturally derived antitumor agent, synergistically suppressed BMP4 expression in the resistant cells. We further confirmed that LDN-193189, a small molecule BMP receptor 1 inhibitor, effectively inhibited tumor growth in a xenograft nude mouse model implanted with the EFGR-TKI-resistant cells. These findings suggest a novel role of BMP4-mediated tumorigenesis in the progression of acquired drug resistance in EGFR-mutant NSCLC cells.

Chromosomal Instability in Tumor Initiation and Development

“…Resistance to anticancer drugs is a complex process (5,(95)(96)(97)(98)(99)(100)(101)(102), and CIN-related phenotypic and genetic diversity in tumors has implications for chemotherapy-resistance including innate and acquired resistance (89). CIN-positive tumors seem to be more sensitive to DNA-damaging agents or radiotherapy (6) stability by using inhibitors of the microtubule-destabilizing kinase, Aurora B (104), may enhance chromosome missegregation; Aurora B inhibitors have shown efficacy in primary as well as taxane-resistant tumors (105,106).…”

Overexpression of AGR2 Is Associated With Drug Resistance in Mutant Non-small Cell Lung Cancers

“…Transwell invasion and migration assays. The cells were posttransfected with siAGR2 or siRNA control for 48 h, and then they were further analyzed using cell migration and invasion assays, as described previously (22). Briefly, the invasion assay was carried out in 24-well Transwell plates (8.0 μm pore size membranes, Corning, NY, USA) for 48 h. The upper surface of the membrane was coated with Matrigel (BD Biosciences, San Jose, CA, USA) and the lower one was covered with 0.2 % gelatin (Sigma Aldrich, St. Louis, MO, USA).…”

“…Immunohistochemistry. Tumor immunohistochemistry analysis was performed according to our previously published procedures (22,23). In brief, sections of the embedded specimens were deparaffinized, rehydrated and subjected to antigen retrieval.…”

“…Microarray expression analysis. Microarray expression analysis was performed according to our previously published procedures (22,23…”

Transcriptome analysis reveals gender-specific differences in overall metabolic response of male and female patients in lung adenocarcinoma

“…Another recent study found that higher expression of nuclear factor erythroid 2-related factor 2 (NRF2)-regulated metabolic gene signature (NRMGS) predicted poor overall survival in eight independent NSCLC cohorts [9]. Furthermore, over-expression of bone morphogenetic protein 4 (BMP4) has been correlated with acquired drug resistance and fatty acid metabolism in NSCLC cells with EGFR mutations [10]. Another study suggested altered glucose transporter 1 (GLUT1)-mediated glucose metabolism as a potential approach for treating NSCLCs resistant to EGFR inhibitors [11].…”