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


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.


CONCLUSIONS
The observed cytotoxicity suggests that reducing BMP signaling is a useful line of attack for therapy of lung cancer.
185 South Orange Ave., Newark, NJ 07103, U.S.A. rogersmb@umdnj.edu.
Anastasios
A
Fotinos
Narayani
N
Nagarajan
Adriano S
AS
Martins
David T
DT
Fritz
Diane
D
Garsetti
Annette T
AT
Lee
Charles C
CC
Hong
Melissa B
MB
Rogers
D000230:Adenocarcinoma / Q000378:metabolism*; D000077192:Adenocarcinoma of Lung; D000970:Antineoplastic Agents / Q000494:pharmacology*; D055396:Bone Morphogenetic Protein 2 / Q000037:antagonists & inhibitors*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D004797:Enzyme-Linked Immunosorbent Assay; D055785:Gene Knockdown Techniques; D006801:Humans; D008175:Lung Neoplasms / Q000378:metabolism*; D035683:MicroRNAs; D020411:Oligonucleotide Array Sequence Analysis; D011720:Pyrazoles / Q000494:pharmacology*; D011743:Pyrimidines / Q000494:pharmacology*; D034622:RNA Interference; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000187:drug effects*
D000970:Antineoplastic Agents; C525718:BMP2 protein, human; D055396:Bone Morphogenetic Protein 2; C554430:LDN 193189; D035683:MicroRNAs; D011720:Pyrazoles; D011743:Pyrimidines
Bone morphogenetic proteins; RNA interference; cell proliferation; cell survival; lung neoplasms; microRNAs; preclinical drug evaluation