Abstract LB-024: Inhibition of bone morphogenetic protein (BMP) type I receptors in lung cancer cells activates the TGFβ signaling cascades which increases Id1 expression by TAK1

Abstract

Abstract Bone morphogenetic protein (BMP) signaling increases Id1 expression while the transforming growth factor (TGF) signaling typically decreases Id1 expression. BMP antagonists decrease growth of cancer through the inhibition of Id1. Both the BMP and TGF signaling pathways activate TGF activated kinase1 (TAK1). TAK1 has been shown to phosphorylate and activate the BMP transcription factor Smad1/5. The purpose of this study was to understand the cross regulation between the BMP and TGFβ signaling pathways in lung cancer cell lines that occurs following the inhibition of BMP signaling. Antagonists targeting the BMP (DMH2, DMH1), TGFβ (SB-505124), and TAK1 ((5Z)-7-Oxozeaenol) signaling cascades were used to examine the cross regulation between these pathways. Here, we show using siRNA and BMP antagonists targeting the type I receptors that upon inhibition of BMP signaling in lung cancer cells, the TGFβ signaling cascade is activated. SB-505124 alone increases Id1 expression in H1299 cells. However, when BMP signaling was inhibited, SB-505124 decreases Id1 expression, which is associated with a decrease expression in pTAK1. When BMP signaling is inhibited, the TGFβ constitutively active alk5 receptor activates TAK1 and increases Id1 expression, which is attenuated with (5Z)-7-Oxozeaenol. A BMP antagonist together with a TGFβ antagonist further enhanced growth suppression. This study reveals that TGFβ signaling can increase the expression of Id1 when BMP signaling is inhibited in lung cancer cells, which is mediated by TAK1. The data suggests that the inhibition of both the BMP and TGF signaling pathways enhances growth suppression of lung cancer cells that involves the downregulation of Id1. Citation Format: John E. Langenfeld, Elaine Langenfeld, Monica Castle. Inhibition of bone morphogenetic protein (BMP) type I receptors in lung cancer cells activates the TGFβ signaling cascades which increases Id1 expression by TAK1. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr LB-024. doi:10.1158/1538-7445.AM2015-LB-024