Targeting bone morphogenetic protein receptor 2 sensitizes lung cancer cells to TRAIL by increasing cytosolic Smac/DIABLO and the downregulation of X-linked inhibitor of apoptosis protein

NeMoyer, Rachel; Mondal, Arindam; Vora, Mehul; Langenfeld, Elaine; Glover, Danea; Scott, Michael J.; Lairson, Lauren; Rongo, Christopher; Augeri, David J.; Peng, Youyi; Jabbour, Salma K.; Langenfeld, John

doi:10.1186/s12964-019-0469-5

Cited by 8 publications

(18 citation statements)

References 53 publications

(93 reference statements)

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“…As previously reported, JL5 caused the mislocalization of BMPR2 to the cytoplasm (Fig. 5E) [22]. We show for the rst time that Ym155 alone also caused an increase in the localization of BMPR2 to the cytosol (Fig.…”

Section: Ym155 Decreases Bmpr2 Expression and Promotes Bmpr2 Mislocalsupporting

confidence: 88%

“…Despite JL5 having a relatively low IC50 for BMPR2 it causes its mislocalization to the cytoplasm at 2.5 mM. This mislocalization does not occur with BMP inhibitors DMH1 or LDN, which have no activity for BMPR2 [22]. The over-expression of XIAP attenuates cell death induced by JL5 [22].…”

Section: Discussionmentioning

confidence: 99%

“…Our prior studies suggested that targeted inhibition of BMPR2 induces cell death mechanisms not seen with the inhibition of BMP type 1 receptors [22]. 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].…”

Section: Discussionmentioning

confidence: 99%

“…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]. Inhibition of BMPR2 and not the type I BMP receptors increases the release of the pro-apoptotic mitochondrial proteins Smac/DIABLO and cytochrome c into the cytosol [22].…”

Section: Introductionmentioning

confidence: 99%

“…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]. Inhibition of BMPR2 and not the type I BMP receptors increases the release of the pro-apoptotic mitochondrial proteins Smac/DIABLO and cytochrome c into the cytosol [22].…”

Section: Introductionmentioning

confidence: 99%

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

Mondal

NeMoyer

Langenfeld

et al. 2020

Preprint

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Background: Bone morphogenetic protein (BMP) is an evolutionarily conserved morphogen that is reactivated in lung carcinomas. BMP receptor inhibitors promote cell death of lung carcinomas by mechanisms not fully elucidated. The studies here reveal novel mechanisms by which the “survivin” inhibitor Ym155 in combination with the BMP receptor inhibitor JL5 synergistically induces death of lung cancer cells. Methods: This study examines the mechanism by which Ym155 in combination with JL5 downregulates BMP signaling and induces cell death of non-small cell lung carcinoma (NSCLC) cell lines. Validation experiments were performed on five passage 0 primary NSCLC cell lines. Results: We found that Ym155, which is reported to be a survivin inhibitor, potently inhibits BMP signaling by causing BMPR2 mislocalization into the cytoplasm and its decreased expression. The combination of Ym155 and the BMP receptor inhibitor JL5 synergistically causes the downregulation of BMP Smad-1/5 dependent and independent signaling and the induction of cell death of lung cancer cell lines and primary lung tumors. Cell death involves the nuclear translocation of apoptosis inducing factor (AIF) from the mitochondria to the nucleus. This causes DNA double stranded breaks independent of caspase activation, which occur only when JL5 and Ym155 are used in combination. Knockdown of BMPR2 together with Ym155 also induced AIF localization to the nucleus. Conclusions: These studies suggest that inhibition of BMPR2 together with Ym155 can induce AIF caspase-independent cell death. AIF caspase-independent cell is an evolutionarily conserved cell death pathway that has never been targeted to induce cell death in cancer cells. These studies provide mechanistic insight of how to target AIF caspase-independent cell death using BMP inhibitors.

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Section: Ym155 Decreases Bmpr2 Expression and Promotes Bmpr2 Mislocalsupporting

confidence: 88%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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

Mondal

NeMoyer

Langenfeld

et al. 2020

Preprint

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Bone morphogenetic protein receptor inhibitors suppress the growth of glioblastoma cells

et al. 2022

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Docking for EP4R antagonists active against inflammatory pain

Gahbauer,

DeLeon,

Braz

et al. 2023

Nat Commun

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The lipid prostaglandin E2 (PGE2) mediates inflammatory pain by activating G protein-coupled receptors, including the prostaglandin E2 receptor 4 (EP4R). Nonsteroidal anti-inflammatory drugs (NSAIDs) reduce nociception by inhibiting prostaglandin synthesis, however, the disruption of upstream prostanoid biosynthesis can lead to pleiotropic effects including gastrointestinal bleeding and cardiac complications. In contrast, by acting downstream, EP4R antagonists may act specifically as anti-inflammatory agents and, to date, no selective EP4R antagonists have been approved for human use. In this work, seeking to diversify EP4R antagonist scaffolds, we computationally dock over 400 million compounds against an EP4R crystal structure and experimentally validate 71 highly ranked, de novo synthesized molecules. Further, we show how structure-based optimization of initial docking hits identifies a potent and selective antagonist with 16 nanomolar potency. Finally, we demonstrate favorable pharmacokinetics for the discovered compound as well as anti-allodynic and anti-inflammatory activity in several preclinical pain models in mice.

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Targeting bone morphogenetic protein receptor 2 sensitizes lung cancer cells to TRAIL by increasing cytosolic Smac/DIABLO and the downregulation of X-linked inhibitor of apoptosis protein

Cited by 8 publications

References 53 publications

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

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

Bone morphogenetic protein receptor inhibitors suppress the growth of glioblastoma cells

Docking for EP4R antagonists active against inflammatory pain

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