Bone morphogenetic protein receptor inhibitors suppress the growth of glioblastoma cells.
Bone morphogenetic protein receptor inhibitors suppress the growth of glioblastoma cells.
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DOI：
10.1007/s11010-022-04383-7
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发表时间：
2022-05
影响因子：
4.3
通讯作者：
Langenfeld J
中科院分区：
文献类型：
--
作者：
Kaye J;Mondal A;Foty R;Jia D;Langenfeld J
胶质母细胞瘤(GBM)是一种侵袭性脑瘤，对化疗和放射具有抵抗力。骨形态发生蛋白(BMP)配体BMP4被认为是一种潜在的治疗GBMS的方法，因为它可以诱导肿瘤干细胞(CSC)分化为星形胶质细胞。ID1被报道具有促进自我更新和抑制CSC分化的作用。在大多数癌症中，ID1在转录水平上受到BMP4的上调，促进了侵袭和茎的形成。这种相互矛盾的数据让人质疑BMP信号在GBM中是抑制生长还是促进生长。我们利用BMP抑制剂DMH1、JL5和Ym155来检测BMP信号在基底膜生长中的作用。DMH1靶向BMP 1型受体，而JL5同时抑制1型和2型BMP受体。Ym155不与BMP受体结合，而是通过诱导BMPR2的降解来抑制BMP信号转导。我们发现JL5、DMH1和Ym155降低了SD2和U87细胞中ID1的表达。JL5和Ym155还可降低BMPR2及其下游靶向凋亡抑制蛋白XIAP的表达。与BMP4配体相比，JL5诱导的细胞死亡和自我更新受到更大程度的抑制。溶酶体抑制剂氯喹增加BMPR2在质膜上的定位，增强JL5诱导的ID1下调和SD2细胞死亡。我们证明了BMP信号在GBM中具有促进生长的作用。这些研究表明有必要开发骨形态发生蛋白抑制剂，并对其作为治疗基底膜的潜在药物进行评估。
Glioblastomas (GBMs) are aggressive brain tumors that are resistant to chemotherapy and radiation. Bone morphogenetic protein (BMP) ligand BMP4 is being examine as a potential therapeutic for GBMs because it induces differentiation of cancer stem cells (CSC) 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 brings 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 down-stream 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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影响因子：
3.7
作者：
Langenfeld E;Hong CC;Lanke G;Langenfeld J
通讯作者：
Langenfeld J
新型和选择性骨形态发生蛋白受体（BMP）抑制剂的合成和结构活性关系从吡唑洛斯[1.5-A]吡胺胺的嘧啶支架衍生而来：ML347的发现ML347作为ALK2对ALK2对ALK3对ALK3的选择性MLPCN探针。
影响因子：
2.7
作者：
Engers, Darren W.;Frist, Audrey Y.;Lindsley, Craig W.;Hong, Charles C.;Hopkins, Corey R.
通讯作者：
Hopkins, Corey R.
影响因子：
37.3
作者：
Augeri DJ;Langenfeld E;Castle M;Gilleran JA;Langenfeld J
通讯作者：
Langenfeld J
影响因子：
4.7
作者：
Langenfeld, EM;Calvano, SE;Langenfeld, J
通讯作者：
Langenfeld, J
影响因子：
5.9
作者：
Carén H;Stricker SH;Bulstrode H;Gagrica S;Johnstone E;Bartlett TE;Feber A;Wilson G;Teschendorff AE;Bertone P;Beck S;Pollard SM
通讯作者：
Pollard SM