Abstract 5263: Src inhibition enhances BMP receptor antagonists downregulation of Id1 and growth suppression of lung cancer cells with a K-Ras mutation.

Abstract The bone morphogenetic protein 2 (BMP2) is aberrantly expressed in 98% of non-small cell lung carcinomas. Our studies show that selective antagonists (DMH1, DMH2, and LDN) of the type I BMP receptors inhibit the proliferation and induce cell death of lung cancer cell lines, which is mediated at least in part by downregulating the expression of Id1 and Id3. The Id proteins are known to regulate essential aspects of tumorigenesis in many carcinomas. The Src signaling pathway has been shown to increase the expression of Id1 in A549 cells. Src regulation of Id1 is mediated through the BMP pathway. Src binds to pSmad 1/5, which enhances its translocation into the nucleus. Src also mediates activity of response elements on the Id1 promoter that also bind pSmad 1/5. The BMP signaling pathway suppresses Src signaling, suggesting feedback inhibition. We examined the ability of a BMP receptor antagonist (DMH2) and a Src antagonist (PP2) to regulate Id1 and Id3 expression in three lung cancer cell lines with a K-Ras mutation (A549,H157,H727) and 3 without a K-Ras mutation (H1299,H865,U1752). PP2 caused a reduction in Id1 and/or Id3 in 2 of the 3 cell lines with a K-Ras mutation (A549,H157). PP2 had no effect or increased the expression of Id1 and Id3 in cell lines without a K-Ras mutation. DMH2 decreased expression of Id1 and Id3 and caused growth suppression of all the cell lines. In the A549 cells, the combination of DMH2 and PP2 caused significantly greater reduction in Id1 promoter activity and growth inhibition than either agent alone. Inhibition of BMP signaling caused an increase in the expression of phosphorylated Src, suggesting feedback regulation. The data suggests that Src inhibition leads to the downregulation of Id expression predominately in lung cancer cells with a K-Ras mutation. Inhibition of BMP signaling with receptor antagonists causes significant downregulation of Id1/Id3 and growth inhibition even in lung cancer cell lines with K-Ras mutations. Inhibition of BMP signaling may activate Src, suggesting that both BMP and Src antagonists are needed to suppress Id expression and inhibit tumor growth. Citation Format: John E. Langenfeld, Elaine Langenfeld. Src inhibition enhances BMP receptor antagonists downregulation of Id1 and growth suppression of lung cancer cells with a K-Ras mutation. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 5263. doi:10.1158/1538-7445.AM2013-5263