title: Bone morphogenetic protein type I receptor antagonists decrease growth and induce cell death of lung cancer cell lines.
abstract: Bone morphogenetic proteins (BMPs) are highly conserved morphogens that are essential for normal development. BMP-2 is highly expressed in the majority of non-small cell lung carcinomas (NSCLC) but not in normal lung tissue or benign lung tumors. The effects of the BMP signaling cascade on the growth and survival of cancer cells is poorly understood. We show that BMP signaling is basally active in lung cancer cell lines, which can be effectively inhibited with selective antagonists of the BMP type I receptors. Lung cancer cell lines express alk2, alk3, and alk6 and inhibition of a single BMP receptor was not sufficient to decrease signaling. Inhibition of more than one type I receptor was required to decrease BMP signaling in lung cancer cell lines. BMP receptor antagonists and silencing of BMP type I receptors with siRNA induced cell death, inhibited cell growth, and caused a significant decrease in the expression of inhibitor of differentiation (Id1, Id2, and Id3) family members, which are known to regulate cell growth and survival in many types of cancers. BMP receptor antagonists also decreased clonogenic cell growth. Knockdown of Id3 significantly decreased cell growth and induced cell death of lung cancer cells. H1299 cells stably overexpressing Id3 were resistant to growth suppression and induction of cell death induced by the BMP antagonist DMH2. These studies suggest that BMP signaling promotes cell growth and survival of lung cancer cells, which is mediated through its regulation of Id family members. Selective antagonists of the BMP type I receptors represents a potential means to pharmacologically treat NSCLC and other carcinomas with an activated BMP signaling cascade.
authors.affiliation: Department of Surgery, Division of Thoracic Surgery, UMDNJ-Robert Wood Johnson Medical School, New Brunswick, New Jersey, USA.
authors.forename: Elaine
authors.initials: E
authors.lastname: Langenfeld
authors.forename: Charles C
authors.initials: CC
authors.lastname: Hong
authors.forename: Gandhi
authors.initials: G
authors.lastname: Lanke
authors.forename: John
authors.initials: J
authors.lastname: Langenfeld
mesh_terms: D055396:Bone Morphogenetic Protein 2 / Q000378:metabolism; D052005:Bone Morphogenetic Protein Receptors, Type I / Q000037:antagonists & inhibitors* / Q000378:metabolism; D001980:Bronchi / Q000473:pathology; D016923:Cell Death / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D002999:Clone Cells; D042783:Endothelial Cells / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D004847:Epithelial Cells / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D055785:Gene Knockdown Techniques; D006801:Humans; D051796:Inhibitor of Differentiation Proteins / Q000378:metabolism; D008175:Lung Neoplasms / Q000378:metabolism* / Q000473:pathology*; D011720:Pyrazoles / Q000494:pharmacology; D011743:Pyrimidines / Q000494:pharmacology; D015398:Signal Transduction / Q000187:drug effects; D051785:Smad Proteins / Q000378:metabolism
chemical_list: D055396:Bone Morphogenetic Protein 2; D051796:Inhibitor of Differentiation Proteins; D011720:Pyrazoles; D011743:Pyrimidines; D051785:Smad Proteins; C516138:dorsomorphin; D052005:Bone Morphogenetic Protein Receptors, Type I