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Bone morphogenetic protein receptor inhibitors suppress the growth of glioblastoma cells

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Abstract

Glioblastomas (GBMs) are aggressive brain tumors that are resistant to chemotherapy and radiation. Bone morphogenetic protein (BMP) ligand BMP4 is being examined as a potential therapeutic for GBMs because it induces differentiation of cancer stem cells (CSCs) to an astrocyte phenotype. ID1 is reported to promote self-renewal and inhibit CSC differentiation. In most cancers, ID1 is transcriptionally upregulated by BMP4 promoting invasion and stemness. This conflicting data bring into question whether BMP signaling is growth suppressive or growth promoting in GBMs. We utilized BMP inhibitors DMH1, JL5, and Ym155 to examine the role of BMP signaling on the growth of GBMs. DMH1 targets BMP type 1 receptors whereas JL5 inhibits both the type 1 and type 2 BMP receptors. Ym155 does not bind the BMP receptors but rather inhibits BMP signaling by inducing the degradation of BMPR2. We show that JL5, DMH1, and Ym155 decreased the expression of ID1 in SD2 and U87 cells. JL5 and Ym155 also decreased the expression of BMPR2 and its downstream target inhibitor of apoptosis protein XIAP. JL5 treatment resulted in significant cell death and suppressed self-renewal to a greater extent than that induced by BMP4 ligand. The lysosome inhibitor chloroquine increases the localization of BMPR2 to the plasma membrane enhancing JL5-induced downregulation of ID1 and cell death in SD2 cells. We show that BMP signaling is growth promoting in GBMs. These studies suggest the need for development of BMP inhibitors and evaluation as potential therapeutic for GBMs.

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Data availability

Data will be made available on reasonable request.

Abbreviations

GBMs:

Glioblastomas

CSCs:

Cancer stem cells

BMPs:

Bone morphogenetic proteins

BMPR:

Bone morphogenetic protein receptor

ID1:

Inhibitor of differentiation protein 1

CO2:

Carbon dioxide

PBS:

Phosphate-buffered saline

NIH:

National Institute of Health

XIAP:

X-linked inhibitor of apoptosis protein

TAK1:

Transforming growth factor-β-activated kinase 1

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Acknowledgements

This work was supported by grants from National Institute of Health (NIH) R01 CA225830 and 3R01CA225830-01S1, and Rutgers University and NIH HealthAdvance grant, #U01HL150852.

Funding

This work was funded by grants from National Institute of Health (NIH) R01 CA225830, 3R01CA225830-01S1, and HealthAdvance/REACH program, Rutgers University and NIH, #U01HL150852.

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  1. Department of Surgery, Rutgers Robert Wood Johnson Medical School, The State University of New Jersey, New Brunswick, NJ, 08903, USA

    Joel Kaye, Arindam Mondal, Ramsey Foty, Dongxuan Jia & John Langenfeld

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Contributions

JK contributed to data acquisition and figure preparation and co-wrote the method section. AM contributed to acquisition of data, co-wrote the methods section, and edited drafted manuscript. RF critically reviewed and edited the manuscript. DJ contributed to data acquisition. JL contributed to study design, preparation of figures, and wrote the manuscript. All authors approved the manuscript.

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Correspondence to John Langenfeld.

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The use of BMP inhibitors and cell lines has been approved by Rutgers University Institutional Biosafety Committee #13-424.

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Kaye, J., Mondal, A., Foty, R. et al. Bone morphogenetic protein receptor inhibitors suppress the growth of glioblastoma cells. Mol Cell Biochem 477, 1583–1595 (2022). https://doi.org/10.1007/s11010-022-04383-7

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