Abstract
Background
Cyclic nucleotides are critical mediators of cellular signalling in glioblastoma. However, the clinical relevance and mechanisms of regulating cyclic nucleotides in glioblastoma progression and recurrence have yet to be thoroughly explored.
Methods
In silico, mRNA, and protein level analyses identified the primary regulator of cyclic nucleotides in recurrent human glioblastoma. Lentiviral and pharmacological manipulations examined the functional impact of cyclic nucleotide signalling in human glioma cell lines and primary glioblastoma cells. An orthotopic xenograft mice model coupled with aspirin hydrogels verified the in vivo outcome of targeting cyclic nucleotide signalling.
Results
Elevated intracellular levels of cGMP, instead of cAMP, due to a lower substrate efflux from ATP-binding cassette sub-family C member 4 (ABCC4) is engaged in the recurrence of glioblastoma. ABCC4 gene expression is negatively associated with recurrence and overall survival outcomes in glioblastoma specimens. ABCC4 loss-of-function activates cGMP-PKG signalling, promoting malignancy in glioblastoma cells and xenografts. Hydrogels loaded with aspirin, inhibiting glioblastoma progression partly by upregulating ABCC4 expressions, augment the efficacy of standard-of-care therapies in orthotopic glioblastoma xenografts.
Conclusion
ABCC4, repressing the cGMP-PKG signalling pathway, is a tumour suppressor in glioblastoma progression and recurrence. Aspirin hydrogels impede glioblastoma progression through ABCC4 restoration and constitute a viable translational approach.
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Data availability
Additional data will be made available upon request.
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Funding
Grant support was provided by the National Science and Technology Council of the Republic of China (Grant Nos. NSTC 110-2628-B-039-006, 112-2628-B-039-004-MY3) and the China Medical University and Hospital (Grant Nos. DMR-112-133, DMR-112-079, CMU112-MF-34, DMR-113-122), the China Medical University Hsinchu Hospital (CMUHCH-DMR-111-007, CMUHCH-DMR-113-010).
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JYC and STW designed the study, performed the experiments, analysed the data and wrote the paper. HJC, HLW, FJL, KYW and YCH performed the cell or animal studies and analysed the data. DCC and CCW provided essential material and analysed the data. CHH conceptualised the project, designed the study, analysed the data, and wrote the paper. All authors had final approval of the submitted versions.
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All animal studies were conducted in accordance with the Institutional Guidelines of China Medical University (Taichung, Taiwan) with the permission of the local Ethical Committee for Animal Experimentation (CMUIACUC- 2016-209). The use of clinical samples was approved by the Institutional Review Board (CMUH108-REC2-062) of China Medical University Hospital (Taichung, Taiwan).
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Chiang, JY., Wei, ST., Chang, HJ. et al. ABCC4 suppresses glioblastoma progression and recurrence by restraining cGMP-PKG signalling. Br J Cancer 130, 1324–1336 (2024). https://doi.org/10.1038/s41416-024-02581-2
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DOI: https://doi.org/10.1038/s41416-024-02581-2