RT Journal Article
SR Electronic
T1 Repurposing clemastine to target glioblastoma cell stemness
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 2022.11.05.515291
DO 10.1101/2022.11.05.515291
A1 Michael A. Sun
A1 Rui Yang
A1 Heng Liu
A1 Wenzhe Wang
A1 Xiao Song
A1 Bo Hu
A1 Nathan Reynolds
A1 Kristen Roso
A1 Lee H. Chen
A1 Paula K. Greer
A1 Stephen T. Keir
A1 Roger E. McLendon
A1 Shi-Yuan Cheng
A1 Darell D. Bigner
A1 David M. Ashley
A1 Christopher J. Pirozzi
A1 Yiping He
YR 2022
UL http://biorxiv.org/content/early/2022/11/05/2022.11.05.515291.abstract
AB Brain tumor-initiating cells (BTICs) and tumor cell plasticity promote glioblastoma (GBM) progression. Here, we demonstrate that clemastine, an over-the-counter drug for treating hay fever and allergy symptoms, effectively attenuated the stemness and suppressed the propagation of primary BTIC cultures bearing PDGFRA amplification. These effects on BTICs were accompanied by altered gene expression profiling indicative of their more differentiated states, resonating with the activity of clemastine in promoting the differentiation of normal oligodendrocyte progenitor cells (OPCs) into mature oligodendrocytes. Functional assays for pharmacological targets of clemastine revealed that Emopamil binding protein (EBP), an enzyme in the cholesterol biosynthesis pathway, is essential for BTIC propagation and a target that mediates the suppressive effects of clemastine. Finally, we showed that a neural stem cell-derived mouse glioma model displaying predominantly proneural features was similarly susceptible to clemastine treatment. Collectively, these results identify pathways essential for maintaining the stemness and progenitor features of GBMs, uncover BTIC dependency on EBP, and suggest that non-oncology, low-toxicity drugs with OPC differentiation-promoting activity can be repurposed to target GBM stemness and aid in their treatment.Competing Interest StatementThe authors have declared no competing interest.