Benjamin Kim

Introduction.  Glioblastomas (GBM) represent approximately half of gliomas and are the most aggressive tumors of the central nervous system.  They portend a poor prognosis, low survival rates, and have limited effective therapies.¹ Despite surgical resection, radiation, and drug therapies, the median survival remains 14-16 months.¹  A key mediator of GBM resistance to therapy may be its ability to regulate reactive oxygen species (ROS).²  Adaptation to oxidative stress in cancer stem cells (CSCs) is mediated by peroxiredoxin (PRDX)-family proteins, particularly PRDX3 isoform, which is stabilized by Prohibitin (PHB).²  Targeting PHB may be a novel strategy to improve therapeutic responses in GBM.  Objective: To review current research on methods and effects of targeting prohibitin to improve efficacy of current treatments for GBM.  Evidence Review: Search of PubMed references between 2019 and 2021 using the terms “glioblastoma” and “prohibitin.”  The review is centered around research conducted by Huang et. al., on the suppression of mitochondrial ROS by prohibitin driving glioblastoma progression and therapeutic resistance.²  Findings:  PHB was localized in the mitochondria and absence of PHB showed in increase in peroxide production.²  PHB was found to be significantly upregulated in GSCs and had a significant contribution to viability and self-renewal capacity in GSCs.²  Effects of a combinatory treatment of Rocaglamide A and radiotherapy had the most efficacy compared to either treatment alone, and more than the combinatory treatment of Temozolomide and radiation.²  Cannabinoid (CBD) and peptidylarginine deiminase (PAD) inhibitor treatments are potential alternatives to reducing PHB levels.  While CBD had a mild effect on reducing PHB levels, PAD3-specific inhibitors (PAD isozyme) had the most efficacy in reducing PHB levels.^3,5  Conclusion.  RocA, CBD, and PAD3-specific inhibitors, in combination with radiotherapy, may be a potential course of treatment for a tumor that is highly radioresistant with poor patient outcomes.  Ultimately, targeting PHB may be the future of novel drug therapies to inhibit tumor cell growth or sensitize GSCs for radiotherapy.

1.  Silantyev, Falzone, L., Libra, M., Gurina, O., Kardashova, K., Nikolouzakis, T., Nosyrev, A., Sutton, C., Mitsias, P., & Tsatsakis, A. (2019). Current and Future Trends on Diagnosis and Prognosis of Glioblastoma: From Molecular Biology to Proteomics. Cells, 8(8), 863. https://doi.org/10.3390/cells8080863
2. Huang, H., Zhang, S., Li, Y. et al. Suppression of mitochondrial ROS by prohibitin drives glioblastoma progression and therapeutic resistance. Nat Commun 12, 3720 (2021). https://doi.org/10.1038/s41467-021-24108-6
3. Kosgodage, U. S., Uysal-Onganer, P., MacLatchy, A., Mould, R., Nunn, A. V., Guy, G. W., Kraev, I., Chatterton, N. P., Thomas, E. L., Inal, J. M., Bell, J. D., & Lange, S. (2019). Cannabidiol affects extracellular vesicle release, miR21 and miR126, and reduces prohibitin protein in glioblastoma multiforme cells. Translational oncology, 12(3), 513–522. https://doi.org/10.1016/j.tranon.2018.12.004
4. Kosgodage, U. S., Uysal-Onganer, P., MacLatchy, A., Kraev, I., Chatterton, N. P., Nicholas, A. P., Inal, J. M., & Lange, S. (2018). Peptidylarginine deiminases post-translationally deiminate prohibitin and modulate extracellular vesicle release and microRNAs in glioblastoma multiforme. International journal of molecular sciences, 20(1), 103. https://doi.org/10.3390/ijms20010103
5. Uysal-Onganer, P., MacLatchy, A., Mahmoud, R., Kraev, I., Thompson, P. R., Inal, J. M., & Lange, S. (2020). Peptidylarginine deiminase isozyme-specific PAD2, PAD3 and PAD4 inhibitors differentially modulate extracellular vesicle signatures and cell invasion in two glioblastoma multiforme cell lines. International journal of molecular sciences, 21(4), 1495. https://doi.org/10.3390/ijms21041495