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BMP4 signaling induces senescence and modulates the oncogenic phenotype of A549 lung adenocarcinoma cells

¹Developmental Biology, ²Hematology/Oncology, and ³Pediatric Surgery Programs, Children's Hospital of Los Angeles Research Institute, Los Angeles, California 90027

Submitted 21 May 2003 ; accepted in final form 28 August 2003

Lung cancer is the most common visceral malignancy in males, with rapidly increasing incidence in females, and a devastatingly poor prognosis. Transforming growth factor (TGF)- has been shown to induce senescence in A549 lung cancer cells, and both TGF- and bone morphogenetic protein (BMP) 2 can suppress the transformed phenotype of A549 cells in vitro. We examined the effects of BMP4, another member of the TGF- superfamily, on specific oncogenic properties of A549 cancer cells. When A549 cancer cells were treated continuously with 100 ng/ml of BMP4, a senescent phenotype was observed after 2 wk of treatment. The BMP-treated cells appeared larger than untreated cells, grew more slowly, had more senescence-associated -galactosidase activity, and had less telomerase activity, as measured by the telomeric repeat amplification protocol assay. Invasion through Engelbreth Holm-Swarm matrix was inhibited in the senescent cell population. Senescent BMP4-treated cells had lower ERK activation, VEGF expression, and Bcl2 expression than wild-type cells, consistent with a less proliferative, less angiogenic phenotype with increased susceptibility to death by apoptosis. BMP4 treatment also resulted in sustained elevation of Smad1. In vivo xenograft studies in the flanks of nude mice confirmed that the BMP-treated cells were significantly less tumorigenic than untreated cells. Direct overexpression of Smad1 using adenoviral constructs resulted in cell death within 5 days. These studies suggest that BMP4 pathway signaling can induce senescence and thus negatively regulate the growth of A549 lung cancer cells.

bone morphogenetic protein 4; senescence-associated -galactosidase activity; telomerase; Engelbreth Holm-Swarm matrix invasion; xenograft tumor

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