Nonreceptor Tyrosine Kinase BMX Maintains Self-Renewal and Tumorigenic Potential of Glioblastoma Stem Cells by Activating STAT3

Abstract

SUMMARY Glioblastomas display cellular hierarchies containing tumor-propagating glioblastoma stem cells (GSCs). STAT3 is a critical signaling node in GSC maintenance but molecular mechanisms underlying STAT3 activation in GSCs are poorly defined. Here we demonstrate that the non-receptor tyrosine kinase BMX activates STAT3 signaling to maintain self-renewal and tumorigenic potential of GSCs. BMX is differentially expressed in GSCs relative to non-stem cancer cells and neural progenitors. BMX knockdown potently inhibited STAT3 activation, expression of GSC transcription factors, and growth of GSC-derived intracranial tumors. Constitutively active STAT3 rescued the effects of BMX downregulation, supporting that BMX signals through STAT3 in GSCs. These data demonstrate that BMX represents a GSC therapeutic target and reinforces the importance of STAT3 signaling in stem-like cancer phenotypes.

Tetraspanin CD9 stabilizes gp130 by preventing its ubiquitin-dependent lysosomal degradation to promote STAT3 activation in glioma stem cells

“…2 GSCs are critical cancer cells that contribute to malignant progression, therapeutic resistance and tumor recurrence in GBM. 5,32 As STAT3 signaling is commonly activated in GSCs, and the BMX-mediated STAT3 activation is required for maintaining the self-renewal and tumorigenic potential of GSCs, 21,22,23 disrupting STAT3 signaling pathway may potently disrupt GSCs and have therapeutic potential. However, targeting STAT3 transcription factor itself is not clinically achievable, as STAT3 is required for other functions in normal cells.…”

“…However, targeting STAT3 transcription factor itself is not clinically achievable, as STAT3 is required for other functions in normal cells. 20,22 Thus, identification of unique upstream regulators controlling STAT3 activation in GSCs may offer new therapeutic targets for developing GSC-specific therapeutics to improve GBM treatment. In this study, we identify tetraspanin CD9 to be preferentially expressed in GSCs and demonstrate that CD9 is crucial for maintaining STAT3 activation in GSCs.…”

“…STAT3 signaling has been shown to be crucial for the maintenance of the stem cell property in ES, somatic stem cells and cancer stem cells, including GSCs. 22,40,41 As STAT3 has essential roles in several cellular activities in normal cells and STAT3 is a transcription factor, direct targeting of STAT3 may cause collateral damage on normal cells, including somatic stem cells. 22,40,41 Our study demonstrated that disrupting CD9 markedly reduced gp130 protein thus inhibited the activation of STAT3 in GSCs.…”

“…20,21 The crucial role of the STAT3 activation in maintaining GSC property has been demonstrated by our laboratory and others. [21][22][23][24] We previously showed that the non-receptor tyrosine kinase bone marrow X-linked non-receptor tyrosine kinase (BMX) mediates STAT3 hyper-activation in GSCs and demonstrated that the BMX-mediated STAT3 activation is required for maintaining GSC self-renewal and tumorigenic potential. 22 However, how BMX kinase is activated by upstream regulators in this pivotal pathway remains elusive.…”

“…[21][22][23][24] We previously showed that the non-receptor tyrosine kinase bone marrow X-linked non-receptor tyrosine kinase (BMX) mediates STAT3 hyper-activation in GSCs and demonstrated that the BMX-mediated STAT3 activation is required for maintaining GSC self-renewal and tumorigenic potential. 22 However, how BMX kinase is activated by upstream regulators in this pivotal pathway remains elusive. Herein we demonstrate that CD9 stabilizes gp130 by blocking its ubiquitin-dependent lysosomal degradation to promote the IL6-gp130-BMX-STAT3 signaling for maintaining GSC selfrenewal and tumorigenic capacity.…”