Inhibition of BMP and of TGFβ receptors downregulates expression of XIAP and TAK1 leading to lung cancer cell death

Abstract

BackgroundBone morphogenetic proteins (BMP) are embryonic proteins that are part of the transforming growth factor (TGFβ) superfamily, which are aberrantly expressed in many carcinomas. Inhibition of BMP receptors with small molecule inhibitors decreases growth and induces death of lung cancer cells, which involves the downregulation of Id1 and Id3 by a Smad dependent mechanism. Developmentally, BMP and TGFβ signaling utilizes Smad-1/5 independent mechanisms to stabilize the expression of X-linked inhibitor of apoptosis protein (XIAP) and activate TGFβ activated kinase 1 (TAK1), which are known to be potent inhibitors of apoptosis. The role of BMP signaling in regulating XIAP and TAK1 in cancer cells is poorly understood. Furthermore, the interaction between the BMP and TGFβ signaling cascades in regulating the activation of TAK1 in cancer cells has not been elucidated.MethodsFeedback regulation between the BMP and TGFβ signaling pathways and their regulation of XIAP, TAK1, and Id1 were examined in lung cancer cells utilizing siRNA and inhibitors targeting BMP type I receptors, inhibitors of BMP and TGFβ type I receptors, and an inhibitor of BMP and TGFβ type I and type II receptors.ResultsWe show that upon inhibition of BMP signaling in lung cancer cells, the TGFβ signaling cascade is activated. Both the BMP and TGFβ pathways activate TAK1, which then increases the expression of Id1. Inhibition of TGFβ signaling increased Id1 expression except when BMP signaling is suppressed, which then causes a dose-related decrease in the expression of Id1. Inhibition of both BMP and TGFβ signaling enhances the downregulation of TAK1. Our data also suggests that the blockade of the BMP type II receptor enhances the downregulation XIAP, which is important in decreasing the activity of TAK1. Knockdown studies demonstrate that both XIAP and TAK1 regulate the survival of lung cancer cells.ConclusionsThis paper highlights that targeting the BMP and TGFβ type I and type II receptors causes a downregulation of XIAP, TAK1, and Id1 leading to cell death of lung cancer cells. Small molecule inhibitors targeting the BMP and TGFβ receptors represents a potential novel means to treat cancer patients.Electronic supplementary materialThe online version of this article (doi:10.1186/s12943-016-0511-9) contains supplementary material, which is available to authorized users.

NF-κB/MAPK activation underlies ACVR1-mediated inflammation in human heterotopic ossification

“…NF-κB is part of the immune defense mechanism and a master regulator of inflammation (97). Increased NF-κB activity is sufficient to drive chronic inflammation (98) and may explain the TLR4 hyperresponsiveness we observed (99). Unexpectedly, FOP macrophages' hyperresponsiveness is likely mediated by 2 different pathways, whether they are monocytes (NF-κB) or differentiated antiinflammatory macrophages (p38).…”

Bone morphogenetic protein 2 (BMP2) induces growth suppression and enhances chemosensitivity of human colon cancer cells

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Bone morphogenetic protein (BMP) receptor inhibitor JL5 synergizes with Ym155 to induce Apoptosis-Inducing Factor (AIF) caspase independent cell death

“…Knockdown of BMPR2 decreases the expression of XIAP in lung cancer cell lines and increases cytosolic cytochrome c and Smac/DIABLO [22]. The BMP inhibitors JL5 and DMH2 decrease the expression of XIAP and cause more cell death than the BMP inhibitors DMH1 and LDN [7,8]. JL5 and DMH2 both demonstrate some inhibition of BMPR2 with in vitro phosphorylation kinase assays with an IC50 of approximately 8 mM [8].…”

“…In non-small cell lung carcinomas (NSCLC), the BMP-2 ligand is over-expressed 17-fold higher in comparison to normal lung tissue and benign lung tumors [4]. A number of studies have shown that BMP signaling has signi cant tumorigenic effects that involve the regulation of cell survival, migration, proliferation, stemness, and angiogenesis, and that high ligand expression correlates with a worse prognosis [3,[5][6][7][8][9][10].…”

“…Recent studies suggest that the BMP signaling cascade mediates cell survival independent of its regulation of Smad-1/5 transcription. Inhibition of BMPR2 decreases the expression of the anti-apoptotic factor X chromosome-linked inhibitor of apoptosis protein (XIAP) and transforming growth factor beta (TGFb) activated kinase 1 (TAK1) [7,20,21]. The inhibition of XIAP is a mechanism by which the BMP inhibitor JL5 creates synergistic cell death in lung cancer cells in combination with TRAIL [22].…”