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2-Methoxyestradiol, an Endogenous 17β-Estradiol Metabolite, Induces Antimitogenic and Apoptotic Actions in Oli-Neu – Oligodendroglial Precursor Cells and Triggers Endoreduplication via p53 Pathway
Version 1
: Received: 19 April 2024 / Approved: 19 April 2024 / Online: 19 April 2024 (13:37:08 CEST)
How to cite:
Schaufelberger, S.A.; Schaettin, M.; Azzarito, G.; Rosselli, M.; Leeners, B.; Dubey, R.K. 2-Methoxyestradiol, an Endogenous 17β-Estradiol Metabolite, Induces Antimitogenic and Apoptotic Actions in Oli-Neu – Oligodendroglial Precursor Cells and Triggers Endoreduplication via p53 Pathway. Preprints2024, 2024041352. https://doi.org/10.20944/preprints202404.1352.v1
Schaufelberger, S.A.; Schaettin, M.; Azzarito, G.; Rosselli, M.; Leeners, B.; Dubey, R.K. 2-Methoxyestradiol, an Endogenous 17β-Estradiol Metabolite, Induces Antimitogenic and Apoptotic Actions in Oli-Neu – Oligodendroglial Precursor Cells and Triggers Endoreduplication via p53 Pathway. Preprints 2024, 2024041352. https://doi.org/10.20944/preprints202404.1352.v1
Schaufelberger, S.A.; Schaettin, M.; Azzarito, G.; Rosselli, M.; Leeners, B.; Dubey, R.K. 2-Methoxyestradiol, an Endogenous 17β-Estradiol Metabolite, Induces Antimitogenic and Apoptotic Actions in Oli-Neu – Oligodendroglial Precursor Cells and Triggers Endoreduplication via p53 Pathway. Preprints2024, 2024041352. https://doi.org/10.20944/preprints202404.1352.v1
APA Style
Schaufelberger, S.A., Schaettin, M., Azzarito, G., Rosselli, M., Leeners, B., & Dubey, R.K. (2024). 2-Methoxyestradiol, an Endogenous 17β-Estradiol Metabolite, Induces Antimitogenic and Apoptotic Actions in Oli-Neu – Oligodendroglial Precursor Cells and Triggers Endoreduplication via p53 Pathway. Preprints. https://doi.org/10.20944/preprints202404.1352.v1
Chicago/Turabian Style
Schaufelberger, S.A., Brigitte Leeners and Raghvendra Krishna Dubey. 2024 "2-Methoxyestradiol, an Endogenous 17β-Estradiol Metabolite, Induces Antimitogenic and Apoptotic Actions in Oli-Neu – Oligodendroglial Precursor Cells and Triggers Endoreduplication via p53 Pathway" Preprints. https://doi.org/10.20944/preprints202404.1352.v1
Abstract
Abstract: Abnormal growth of oligodendrocyte precursor cells (OPCs) importantly contributes to the progression of glioblastoma tumors. Hence, molecules that block OPC growth may be of therapeutic importance in treating gliomas. 2-methoxyestradiol (2ME), an endogenous tubulin interacting metabolite of estradiol is effective against multiple proliferative disorders. Based on its anti-carcinogenic and anti-angiogenic actions it is undergoing phase II clinical trials. We hy-pothesize that 2ME may prevent glioma growth by targeting OPC growth. Here we tested this hypothesis by assessing the impact of 2ME on growth of OPC cell line “Oli-neu” and dissected the underlying mechanism(s). Treatment with 2ME inhibited OPC growth in a concentra-tion-dependent manner and accompanied with significant upregulation in expression of p21 and p27, negative cell cycle regulators. Moreover, treatment with 2ME altered OPC morphology from multi-arm processes to rounded cells. At concentrations of 1uM and greater 2ME induced apoptosis with increased expression of caspase 3, PARP and caspase-7 fragments, externalized phosphatidylserine staining / apopercentage and increased mitochondrial activity. Flow-cytometry and microscopic analysis demonstrated that 2ME triggers endoreduplication in a concentration-dependent fashion. Importantly, 2ME induced cyclin E, JNK1/2 and p53 expres-sion as well as OPC cell fusion, key mechanisms driving endoreduplication or whole-genome duplication. Importantly, inhibition of p53 with pfithrin-α rescued 2ME-induced endoreduplica-tion. The pro-apoptotic and endoreduplication actions of 2ME were accompanied with upregula-tion of survivin, cyclin A, Cyclin B, Cyclin D2, ppRB. Taken together our findings provide evi-dence that 2ME not only inhibits OPC growth and triggers apoptosis, but also activates OPCs in a survival - fight or flight mode leading to endoreduplication. This inherent survival character-istic of OPCs may, in part be responsible for drug resistance in gliomas as observed for many tubulin interacting drugs. Importantly, the fate of OPCs after 2ME treatment may depend on cell-cycle status of the individual cells. Combining tubulin-interfering molecules with drugs, such as pfithrin-α, that inhibit endoreduplication may help inhibit OPC/glioma growth and lim-it drug resistance.
Copyright:
This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
