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Current Drug Targets

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ISSN (Print): 1389-4501
ISSN (Online): 1873-5592

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Perspective

A Perspective on Bone Morphogenetic Proteins: Dilemma behind Cancer- related Responses

Author(s): Anmol Kapoor and Chandi C. Mandal*

Volume 24, Issue 5, 2023

Published on: 08 March, 2023

Page: [382 - 387] Pages: 6

DOI: 10.2174/1389450124666230201144605

Price: $65

Abstract

Bone morphogenetic proteins are a center of serious concern and are known to execute various cancer-related issues. The BMP signaling cascades have become more unpredictable as a result of their pleiotropic and risky characteristics, particularly when it comes to cancer responses. This perspective discusses the current therapeutic implications, emphasizes different cellular aspects that impact the failures of the current drug treatments, and speculates on future research avenues that include novel strategies like metabolomic studies and bio-mimetic peptide therapeutics to mitigate cancerous outcomes.

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[1]
Urist MR. Bone: Formation by autoinduction. Science 1965; 150(3698): 893-9.
[http://dx.doi.org/10.1126/science.150.3698.893] [PMID: 5319761]
[2]
Wozney JM, Rosen V, Celeste AJ, et al. Novel regulators of bone formation: molecular clones and activities. Science 1988; 242(4885): 1528-34.
[http://dx.doi.org/10.1126/science.3201241] [PMID: 3201241]
[3]
Yang J, Ueharu H, Mishina Y. Energy metabolism: A newly emerging target of BMP signaling in bone homeostasis. Bone 2020; 138: 115467.
[http://dx.doi.org/10.1016/j.bone.2020.115467] [PMID: 32512164]
[4]
Baboota RK, Blüher M, Smith U. Emerging role of bone morphogenetic protein 4 in metabolic disorders. Diabetes 2021; 70(2): 303-12.
[http://dx.doi.org/10.2337/db20-0884] [PMID: 33472940]
[5]
Bach DH, Park HJ, Lee SK. The dual role of bone morphogenetic proteins in cancer. Mol Ther Oncolytics 2018; 8: 1-13.
[http://dx.doi.org/10.1016/j.omto.2017.10.002] [PMID: 29234727]
[6]
Zhang YE. Non-smad pathways in TGF-β signaling. Cell Res 2009; 19(1): 128-39.
[http://dx.doi.org/10.1038/cr.2008.328] [PMID: 19114990]
[7]
Derynck R, Zhang YE. Smad-dependent and Smad-independent pathways in TGF-β family signalling. Nature 2003; 425(6958): 577-84.
[http://dx.doi.org/10.1038/nature02006] [PMID: 14534577]
[8]
Garulli C, Kalogris C, Pietrella L, et al. Dorsomorphin reverses the mesenchymal phenotype of breast cancer initiating cells by inhibition of bone morphogenetic protein signaling. Cell Signal 2014; 26(2): 352-62.
[9]
Gao J, Muroya R, Huang F, et al. Bone morphogenetic protein induces bone invasion of melanoma by epithelial-mesenchymal transition via the Smad1/5 signaling pathway. Lab Invest 2021; 101(11): 1475-83.
[10]
Carvalho D, Taylor KR, Olaciregui NG, et al. ALK2 inhibitors display beneficial effects in preclinical models of ACVR1 mutant diffuse intrinsic pontine glioma. Commun Biol 2019; 2: 156.
[11]
Hao J, Lee R, Chang A, et al. DMH1, a small molecule inhibitor of BMP type i receptors, suppresses growth and invasion of lung cancer. PLoS One 2014; 9(6): e90748.
[12]
Engers DW, Frist AY, Lindsley CW, Hong CC, Hopkins CR. Synthesis and structure-activity relationships of a novel and selective bone morphogenetic protein receptor (BMP) inhibitor derived from the pyrazolo[1.5-a]pyrimidine scaffold of dorsomorphin: the discovery of ML347 as an ALK2 versus ALK3 selective MLPCN probe. Bioorg Med Chem Lett 2013; 23(11): 3248-52.
[13]
Kerr G, Sheldon H, Chaikuad A, et al. A small molecule targeting ALK1 prevents Notch cooperativity and inhibits functional angiogenesis. Angiogenesis 2015; 18(2): 209-17.
[14]
Sanvitale CE, Kerr G, Chaikuad A, et al. A new class of small molecule inhibitor of BMP signaling. PLoS One 2013; 8(4): e62721.
[15]
Tsugawa D, Oya Y, Masuzaki R, et al. Specific activin receptor-like kinase 3 inhibitors enhance liver regeneration. J Pharmacol Exp Ther 2014; 351(3): 549-8.
[16]
Williams E, Bagarova J, Kerr G, et al. Saracatinib is an efficacious clinical candidate for fibrodysplasia ossificans progressiva. JCI Insight 2021; 6(8)
[17]
Hawinkels LJ, de Vinuesa, AG , Paauwe M, Kruithof-de Julio M, Wiercinska E, Pardali E, et al. Activin receptor-like kinase 1 ligand trap reduces microvascular density and improves chemotherapy efficiency to various solid tumors. Clin Cancer Res 2016; 22(1): 96-106.
[18]
Humbert M, McLaughlin V, Gibbs JSR, et al. Sotatercept for the Treatment of Pulmonary Arterial Hypertension. N Engl J Med 2021; 384(13): 1204-5.
[19]
Strong AL, Spreadborough PJ, Dey D, et al. BMP ligand trap ALK3-Fc attenuates osteogenesis and heterotopic ossification in blast-related lower extremity trauma. Stem Cells Dev 2021; 30(2): 91-105.
[20]
Vanhoutte F, Liang S, Ruddy M, et al. Pharmacokinetics and pharmacodynamics of garetosmab (Anti-Activin A): Results from a first-in-human phase 1 study. J Clin Pharmacol 2020; 60(11): 1424-31.
[21]
Ruiz S, Chandakkar P, Zhao H, et al. Tacrolimus rescues the signaling and gene expression signature of endothelial ALK1 loss-of-function and improves HHT vascular pathology. Hum Mol Genet 2017; 26(4): 4786-98.
[22]
Weidner H, Yuan Gao, V , Dibert D, et al. CK2.3, a Mimetic Peptide of the BMP Type I Receptor, Increases Activity in Osteoblasts over BMP2. Int J Mol Sci 2019; 20(23)
[23]
Shimono K, Tung WE, Macolino C, et al. Potent inhibition of heterotopic ossification by nuclear retinoic acid receptor-γ agonists. Nat Med 2011; 17(4): 454-60.
[24]
Johnson DW, Berg JN, Baldwin MA, et al. Mutations in the activin receptor–like kinase 1 gene in hereditary haemorrhagic telangiectasia type 2. Nat Genet 1996; 13(2): 189-95.
[http://dx.doi.org/10.1038/ng0696-189] [PMID: 8640225]
[25]
Shore EM, Xu M, Feldman GJ, et al. A recurrent mutation in the BMP type I receptor ACVR1 causes inherited and sporadic fibrodysplasia ossificans progressiva. Nat Genet 2006; 38(5): 525-7.
[http://dx.doi.org/10.1038/ng1783] [PMID: 16642017]
[26]
Howe JR, Bair JL, Sayed MG, et al. Germline mutations of the gene encoding bone morphogenetic protein receptor 1A in juvenile polyposis. Nat Genet 2001; 28(2): 184-7.
[http://dx.doi.org/10.1038/88919] [PMID: 11381269]
[27]
Gräf S, Haimel M, Bleda M, et al. Identification of rare sequence variation underlying heritable pulmonary arterial hypertension. Nat Commun 2018; 9(1): 1416.
[http://dx.doi.org/10.1038/s41467-018-03672-4] [PMID: 29650961]
[28]
Kim BR, Oh SC, Lee DH, et al. BMP-2 induces motility and invasiveness by promoting colon cancer stemness through STAT3 activation. Tumour Biol 2015; 36(12): 9475-86.
[http://dx.doi.org/10.1007/s13277-015-3681-y] [PMID: 26124007]
[29]
Zhang Y, Chen X, Qiao M, et al. Bone morphogenetic protein 2 inhibits the proliferation and growth of human colorectal cancer cells. Oncol Rep 2014; 32(3): 1013-20.
[http://dx.doi.org/10.3892/or.2014.3308] [PMID: 24993644]
[30]
Xu T, Yu C, Sun J, et al. Bone morphogenetic protein-4-induced epithelial-mesenchymal transition and invasiveness through Smad1-mediated signal pathway in squamous cell carcinoma of the head and neck. Arch Med Res 2011; 42(2): 128-37.
[http://dx.doi.org/10.1016/j.arcmed.2011.03.003] [PMID: 21565626]
[31]
Kim IY, Lee DH, Lee DK, et al. Restoration of bone morphogenetic protein receptor type II expression leads to a decreased rate of tumor growth in bladder transitional cell carcinoma cell line TSU-Pr1. Cancer Res 2004; 64(20): 7355-60.
[http://dx.doi.org/10.1158/0008-5472.CAN-04-0154] [PMID: 15492256]
[32]
Tamada H, Kitazawa R, Gohji K, Kitazawa S. Epigenetic regulation of human bone morphogenetic protein 6 gene expression in prostate cancer. J Bone Miner Res 2001; 16(3): 487-96.
[http://dx.doi.org/10.1359/jbmr.2001.16.3.487] [PMID: 11277266]
[33]
Liu G, Liu YJ, Lian WJ, Zhao ZW, Yi T, Zhou HY. Reduced BMP6 expression by DNA methylation contributes to EMT and drug resistance in breast cancer cells. Oncol Rep 2014; 32(2): 581-8.
[http://dx.doi.org/10.3892/or.2014.3224] [PMID: 24890613]
[34]
Kodach LL, Wiercinska E, de Miranda NFCC, et al. The bone morphogenetic protein pathway is inactivated in the majority of sporadic colorectal cancers. Gastroenterology 2008; 134(5): 1332-1341.e3.
[http://dx.doi.org/10.1053/j.gastro.2008.02.059] [PMID: 18471510]
[35]
Hahn SA, Schutte M, Shamsul Hoque ATM, et al. DPC4, a candidate tumor suppressor gene at human chromosome 18q21.1. Science 1996; 271(5247): 350-3.
[http://dx.doi.org/10.1126/science.271.5247.350] [PMID: 8553070]
[36]
Fukuda T, Fukuda R, Miyazono K, Heldin CH. Tumor promoting effect of BMP signaling in endometrial cancer. Int J Mol Sci 2021; 22(15): 7882.
[http://dx.doi.org/10.3390/ijms22157882] [PMID: 34360647]
[37]
de Vinuesa AG, Bocci M, Pietras K, ten Dijke P. Targeting tumour vasculature by inhibiting activin receptor-like kinase (ALK)1 function. Biochem Soc Trans 2016; 44(4): 1142-9.
[http://dx.doi.org/10.1042/BST20160093] [PMID: 27528762]
[38]
Mandal CC, Ganapathy S, Gorin Y, et al. Reactive oxygen species derived from Nox4 mediate BMP2 gene transcription and osteoblast differentiation. Biochem J 2011; 433(2): 393-402.
[http://dx.doi.org/10.1042/BJ20100357] [PMID: 21029048]
[39]
Mandal CC, Das F, Ganapathy S, Harris SE, Ghosh Choudhury G, Ghosh-Choudhury N. Bone morphogenetic Protein-2 (BMP-2) activates nfatc1 transcription factor via an autoregulatory loop involving Smad/Akt/Ca2+ signaling. J Biol Chem 2016; 291(3): 1148-61.
[http://dx.doi.org/10.1074/jbc.M115.668939] [PMID: 26472929]
[40]
Sharma T, Sharma A, Maheshwari R, Pachori G, Kumari P, Mandal CC. Docosahexaenoic Acid (DHA) inhibits bone morphogenetic protein-2 (BMP-2) elevated osteoblast potential of metastatic breast cancer (MDA-MB-231) cells in mammary microcalcification. Nutr Cancer 2020; 72(5): 873-83.
[http://dx.doi.org/10.1080/01635581.2019.1651879] [PMID: 31409173]
[41]
Ghosh-Choudhury N, Mandal CC, Das F, Ganapathy S, Ahuja S, Ghosh Choudhury G. c-Abl-dependent molecular circuitry involving Smad5 and phosphatidylinositol 3-kinase regulates bone morphogenetic protein-2-induced osteogenesis. J Biol Chem 2013; 288(34): 24503-17.
[http://dx.doi.org/10.1074/jbc.M113.455733] [PMID: 23821550]
[42]
Easwaran H, Tsai HC, Baylin SB. Cancer epigenetics: tumor heterogeneity, plasticity of stem-like states, and drug resistance. Mol Cell 2014; 54(5): 716-27.
[http://dx.doi.org/10.1016/j.molcel.2014.05.015] [PMID: 24905005]
[43]
Emwas AH, Szczepski K, Poulson BG, et al. NMR as a “Gold Standard” method in drug design and discovery. Molecules 2020; 25(20): 4597.
[http://dx.doi.org/10.3390/molecules25204597] [PMID: 33050240]

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