BMP9 inhibits the growth and migration of lung adenocarcinoma A549 cells in a bone marrow stromal cell-derived microenvironment through the MAPK/ERK and NF-κB pathways

Abstract

Bone is the most common distant metastatic site of lung cancer, and is particularly prone to osteolytic damage. Soluble factors secreted from bone marrow-derived cells and tumor cells contribute to the growth and metastasis of cancer cells, and enhance osteolytic damage. BMP9, as the most powerful osteogenetic factor of the bone morphogenetic protein (BMP) family, can regulate the development of various tumors. However, the effects and underlying mechanisms of BMP9 in regards to lung cancer and the bone metastatic microenvironment are poorly understood. Here, we determined the inhibitory effects of BMP9 on the proliferation and migration of lung adenocarcinoma A549 cells. When a co-culture system of A549 cells and bone marrow-derived cells (HS-5) was established, it was shown that HS-5 cells promoted the proliferation and migration of A549 cells, and metastasis and osteoclast-related factors IL-6 and IL-8 were increased in the A549 and HS-5 cells. However, BMP9 inhibited the proliferation and migration of the A549 cells in the bone microenvironment, and decreased the levels of IL-6 and IL-8. In addition, mitogen-activated protein kinase (MAPK/ERK) and nuclear factor-κB (NF-κB) signaling pathway may be involved in these effects.

BMP9 counteracts the tumorigenic and pro-angiogenic potential of glioblastoma

“…The first effect of BMP9 that we observed in our study was a clear-cut reduction of GBM cell proliferation. A similar effect has already been reported for BMP9 in lung, gastric and breast cancers in which PI3K/AKT and MAPK pathway inhibition was suggested to play a crucial role [17,34,35]. Here we show that inhibition of PI3K/AKT and MAPK signalings results in the accumulation of the cell cycle inhibitors p21 and p27, molecularly corroborating our results.…”

“…S2B). In order to deepen the molecular events underlying these effects, we analyzed the activation status of multiple intracellular effectors involved in the regulation of cell survival and proliferation, demonstrating a BMP9-mediated deactivation of PI3K, AKT and ERK1/2 as previously suggested [17,34,35], finally resulting in the up-regulation of the cell cycle inhibitors p21 and p27 ( Fig. 2d).…”

“…BMPs are members of the TGF-β family of ligands involved in tissue development and cell type specification [13,14]. BMPs have been described to induce differentiation and inhibit proliferation and invasiveness in various cancers [15][16][17][18] including GBM [5,[19][20][21][22][23][24]. In addition, they were identified as molecular regulators of angiogenesis and vascular development [25], with BMP9 mutations being the major cause of some vascular syndromes [26].…”

“…Indeed, the BMP9 receptor Activin receptor-Like Kinase 1 (ALK1) is specifically expressed in endothelial cells (EC) [27,28]. Given these reported effects of BMP9 on both tumor and EC [16,17,[27][28][29], it may be exploited as an effective anti-cancer agent in GBM.…”

USP4 expression independently predicts favorable survival in lung adenocarcinoma

“…Activation of the NF‐κB signaling pathway is closely related to tumorigenesis of lung cancer . USP4 is also demonstrated as a negative regulator of TNF‐α‐mediated gene expression, such as IL6, IL8 and COX2 (11), which are associated with angiogenesis, growth and migration of LUAD cells . In addition, UPS4 can suppress TNF‐ α ‐induced cell migration in LUAD cancer cells .…”