Overexpression of TGF-β1 by Glioblastoma Stem Cells Under the Influence of 2-Microglobulin Drives Mechanism of MGMT Mediated Temozolomide Resistance
Background: Glioblastoma multiforme (GBM) is the most common primary intracranial malignancy in adults.1 GBM is a grade IV astrocytoma with a dismal mean survival time and two-year survival rate of 9-15 months and less than 10%, respectively.2,3,4,5 The current standard of care for GBM is surgical resection followed by concomitant treatment with the chemotherapeutic temozolomide (TMZ).1,6,7,8 TMZ is an alkylating agent responsible for adding alkyl groups to the nitrogen base guanine in DNA, inducing base pair mismatches and subsequent cell death.1,2 It has been well-documented that O6-methylguanine-DNA methyltransferase, MGMT, is an endogenous protein responsible for repairing DNA damage induced by TMZ, thus promoting GBM cell survival and growth.1,2,4,6-9 Increased 2-microglobulin signaling and overexpression of TGF-β1 have been observed in TMZ resistant GBM.5,8,9 These findings could highlight possible therapeutic targets to increase TMZ sensitivity and improve patient outcomes.
Objective: In this review, we investigated the biomolecular mechanisms behind MGMT-induced TMZ resistance in GBM cells.
Search Methods: Online research was performed through the PubMed MeSH Database for recent articles published between 2017-2022 using the terms: “Glioblastoma”, “drug therapy”, “immunology”, “pathology”, and “therapy”. The keywords “drug resistance” were also used.
Results: Studies demonstrate that MGMT is the most prominent factor in TMZ resistance and that overexpressed signaling pathways may be the root cause.2 Preferential expression of 2-microglobulin by glioblastoma stem cells (GSCs) was observed in surgically resected GBM cells.5 2-microglobulin was subsequently found to promote maintenance and growth of GSCs through activation of the PI3K/AKT signaling cascade with downstream upregulation of the growth-promoting MYC gene.5 MYC directly influenced the upregulation of TGF-β1, and knockdown 2-microglobulin correlated with decreased levels of MYC and TGF-β1.5 Overexpression of TGF-β1 demonstrated increased TMZ resistance in both in vitro and in vivo models.9 TGF-β1 alters miRNA-198 processing by disrupting K-homology splicing protein (KSRP) function.9 KSRP is responsible for the maturation of miRNA-198.9 TGF-β1 directly upregulated competitive inhibitors of the KSRP/miRNA-198 interaction, decreased KSRP affinity for miRNA-198, and decreased nucleocytoplasmic of KSRP into the nucleus.9 MiRNA-198 was found to have a predicted binding site in the 3’-UTR of MGMT mRNA, demonstrating its direct functions in post-transcriptional silencing of the MGMT gene.4 Both cell and mouse models exhibiting upregulated miRNA-198 showed significant increases in TMZ sensitivity and TMZ-induced growth inhibition in vivo.4 One study found that TGF-β1 inhibitors, such as OKN-007, could serve as an adjunct therapy to TMZ to modulate its effectiveness.8 This study saw significant increases in survival and decreases in tumor volume for in vivo models that underwent a combination therapy including OKN-007 and TMZ.8
Conclusions: Studies have demonstrated a detailed mechanism that controls MGMT upregulation in TMZ-resistant GBM cells leading to dismal prognoses. Inhibition of TGF-β1, one of the major contributors in this pathway, shows considerable promise in reversing MGMT-mediated TMZ resistance. Further investigation of drug therapies targeting TGF-β1 or other mediators of this mechanism could lead to significant improvements in the treatment of GBM and patient outcomes.
- Melhem JM, Detsky J, Lim-Fat MJ, Perry JR. Updates in IDH-Wildtype Glioblastoma. Neurotherapeutics. 2022;19(6):1705-1723. doi:10.1007/s13311-022-01251-6
- Tomar MS, Kumar A, Srivastava C, Shrivastava A. Elucidating the mechanisms of Temozolomide resistance in gliomas and the strategies to overcome the resistance. Biochim Biophys Acta Rev Cancer. 2021;1876(2):188616. doi:10.1016/j.bbcan.2021.188616
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- Nie E, Jin X, Wu W, et al. MiR-198 enhances temozolomide sensitivity in glioblastoma by targeting MGMT. J Neurooncol. 2017;133(1):59-68. doi:10.1007/s11060-017-2425-9
- Li D, Zhang Q, Li L, et al. β2-Microglobulin Maintains Glioblastoma Stem Cells and Induces M2-like Polarization of Tumor-Associated Macrophages. Cancer Res. 2022;82(18):3321-3334. doi:10.1158/0008-5472.CAN-22-0507
- Szylberg M, Sokal P, Śledzińska P, et al. MGMT Promoter Methylation as a Prognostic Factor in Primary Glioblastoma: A Single-Institution Observational Study. Biomedicines. 2022;10(8):2030. Published 2022 Aug 20. doi:10.3390/biomedicines10082030
- McKinnon C, Nandhabalan M, Murray SA, Plaha P. Glioblastoma: clinical presentation, diagnosis, and management. BMJ. 2021;374:n1560. Published 2021 Jul 14. doi:10.1136/bmj.n1560
- Towner RA, Smith N, Saunders D, et al. OKN-007 Increases temozolomide (TMZ) Sensitivity and Suppresses TMZ-Resistant Glioblastoma (GBM) Tumor Growth. Transl Oncol. 2019;12(2):320-335. doi:10.1016/j.tranon.2018.10.002
- Nie E, Jin X, Miao F, et al. TGF-β1 modulates temozolomide resistance in glioblastoma via altered microRNA processing and elevated MGMT. Neuro Oncol. 2021;23(3):435-446. doi:10.1093/neuonc/noaa198