期刊
AMERICAN JOURNAL OF PHYSIOLOGY-LUNG CELLULAR AND MOLECULAR PHYSIOLOGY
卷 286, 期 1, 页码 L81-L86出版社
AMER PHYSIOLOGICAL SOC
DOI: 10.1152/ajplung.00160.2003
关键词
bone morphogenetic protein 4; senescence-associated beta-galactosidase activity; telomerase; Engelbreth Holm-Swarm matrix invasion; xenograft tumor
资金
- NATIONAL HEART, LUNG, AND BLOOD INSTITUTE [R01HL044977, P01HL060231, R01HL068597, R01HL044060, R01HL061286] Funding Source: NIH RePORTER
- NHLBI NIH HHS [R01 HL068597, R01 HL061286-03, HL-60231, HL-44977, R01 HL068597-01, HL-61286, HL-68597, HL-44060, R01 HL061286] Funding Source: Medline
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)-beta has been shown to induce senescence in A549 lung cancer cells, and both TGF-beta 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-beta 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 beta-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.
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