Journal
CELL PROLIFERATION
Volume 53, Issue 1, Pages -Publisher
WILEY
DOI: 10.1111/cpr.12732
Keywords
AQP4; gamabufotalin; glioblastoma multiforme; temozolomide
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Funding
- Distinguished Professor Project of Liaoning Province, Special Grant for Translational Medicine, Dalian Medical University [2015002]
- Basic research projects in colleges and universities of Liaoning Province [LQ2017033]
- Liaoning province innovation talents support program in Colleges and Universities [LR2016023]
- National Natural Science Foundation of China [81372714, 81672480, 81802506, 81872065]
- Natural Science Foundation of Liaoning Province [201602244]
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Objectives Temozolomide (TMZ) is one of the most commonly used clinical drugs for glioblastoma (GBM) treatment, but its drug sensitivity needs to be improved. Gamabufotalin (CS-6), the primary component of the traditional Chinese medicine ChanSu, was shown to have strong anti-cancer activity. However, more efforts should be directed towards reducing its toxicity or effective treatment doses. Methods Target fishing experiment, Western blotting, PCR, confocal immunofluorescence and molecular cloning techniques were performed to search for possible downstream signalling pathways. In addition, GBM xenografts were used to further determine the potential molecular mechanisms of the synergistic effects of CS-6 and TMZ in vivo. Results Mechanistic research revealed a negative feedback loop between ATP1A3 and AQP4 through which CS-6 inhibited GBM growth and mediated the synergistic treatment effect of CS-6 and TMZ. In addition, by mutating potential amino acid residues of ATP1A3, which were predicted by modelling and docking to interact with CS-6, we demonstrated that abrogating hydrogen bonding of the amino acid Thr794 interferes with the activation of ATP1A3 by CS-6 and that the Thr794Ala mutation directly affects the synergistic treatment efficacy of CS-6 and TMZ. Conclusions As the main potential target of CS-6, ATP1A3 activation critically depends on the hydrogen bonding of Thr794 with CS-6. The combination of CS-6 and TMZ could significantly reduce the therapeutic doses and promote the anti-cancer efficacy of CS-6/TMZ monotherapy.
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