Tyrosine kinase Eph receptor A6 sensitizes glioma‐initiating cells towards bone morphogenetic protein‐induced apoptosis

Abstract

Bone morphogenetic protein (BMP) signaling plays important roles in glioblastoma multiforme (GBM), a lethal form of brain tumor. BMP reduces GBM tumorigenicity through its differentiation‐ and apoptosis‐inducing effects on glioma‐initiating cells (GIC). However, some GIC do not respond to the tumor suppressive effects of BMP. Using a phosphoreceptor tyrosine kinase array, we found that EPHA6 (erythropoietin‐producing hepatocellular carcinoma receptor A6) phosphorylation was regulated by BMP‐2 signaling in some GIC. Analysis of The Cancer Genome Atlas showed that EPHA6 expression was lower in patients with GBM than in the normal brain, and that high EPHA6 expression was correlated with better prognosis. EPHA6 receptor increased the susceptibility of both sensitive and resistant GIC to BMP‐2‐induced apoptosis. The cooperative effect on apoptosis induction depended on the kinase activity of BMP type I receptor but was independent of EPHA6 kinase function. Overexpression of the EPHA6 receptor in GIC resulted in the formation of a protein complex of EPHA6 receptor and the BMP type I receptor ALK‐2, which was associated with BMP‐induced apoptosis in GIC. Intracranial injection of GIC into nude mice showed that gain‐of‐function of EPHA6 together with BMP‐2 pretreatment slowed GBM tumor progression in the mouse brain and promoted mouse survival. In summary, EPHA6 together with BMP‐2 signaling led to apoptotic cell death in GIC, and thus is a putative tumor suppressor in GBM.

Bone Morphogenetic Protein 7 Effect on Human Glioblastoma Cell Transmigration and Migration

“…BMPs, e.g., BMP2/4/7, and their downstream signaling, type I receptor [ 26 , 27 ], have been found for their potential inhibitory roles in glioma tumorigenicity since 2006 [ 28 ]. However, after extensive investigations, although most of the studies have demonstrated their glioma-suppressor roles [ 9 , 10 , 11 , 12 , 13 , 14 , 15 ], accumulating data indicated that the BMPs effect on glioma development might be tumor phenotype-dependent [ 24 ].…”

TrkB induced metastatic potential of cancer by suppression of BMP mediated tumor inhibitory activity

“…Moreover, estrogen treatment increases the reduction of BMPRI [10]. Furthermore, expression of BMPRI or BMPRII exhibited significant loss in patients of poorly differentiated prostate cancer, renal cell carcinoma, urinary bladder cancer [5,11,12] and BMPRI expression frequently reduced and associated with poor survival in pancreatic cancer patients and inactivation of BMP signaling induces invasiveness of tumor [6] and BMP-2 induced apoptosis of glioma by induction of BMPRI [13]. However, other studies suggest that BMP signaling engaged in tumorigenesis and metastasis of tumors as tumor promotor.…”

PRRX1 induced by BMP signaling decreases tumorigenesis by epigenetically regulating glioma‐initiating cell properties via DNA methyltransferase 3A

“…Gremlin1, an extracellular antagonist of BMPs, is secreted by GICs and maintains their stem cell‐like properties by inhibiting endogenous BMP signaling [ 19 ]. We showed that, among the three BMP type I receptors expressed in GICs, ALK‐2 plays a major role in apoptosis regulation [ 20 ] and that cooperation with EphA6 tyrosine kinase receptor sensitizes some resistant GICs for BMP‐induced apoptosis [ 28 ]. However, because of the heterogeneity of glioblastoma cells, certain other BMP target molecules may also be critically involved in differentiation and apoptosis of GICs, and it remains to be elucidated how the stem cell‐like properties of GICs are regulated by BMPs.…”