Bone morphogenetic protein-focused strategies to induce cytotoxicity in lung cancer cells.

Abstract

BACKGROUND: High bone morphogenetic protein (BMP)-2 expression in lung carcinoma correlates with poor patient prognosis. The present study explored strategies to repress BMP signaling. MATERIALS AND METHODS: The cytotoxicity of BMP2-knockdown, dorsomorphin derivatives, and microRNAs was tested in transformed and non-transformed lung cells. Microarray analyses of 1,145 microRNAs in A549 lung adenocarcinoma cells and two other transformed lung cell types relative to BEAS-2B bronchial epithelial cells were performed. RESULTS: Reduced BMP2 synthesis inhibited A549 cell growth. The dorsomorphin derivative LDN-193189, but not DMH1 or DMH4, was strongly cytotoxic towards A549 cells, but not towards BEAS-2B cells. Microarray analysis revealed that 106 miRNAs were down-regulated and 69 miRNAs were up-regulated in the three transformed lines. Three down-regulated miRNAs, hsa-mir-34b, hsa-mir-34c-3p, and hsa-miR-486-3p, repressed a BMP2 reporter gene and were cytotoxic in A549 cells, but not towards BEAS-2B cells. CONCLUSION: The observed cytotoxicity suggests that reducing BMP signaling is a useful line of attack for therapy of lung cancer.