Human enzyme-mediated, systemic depletion of methionine for glioblastoma treatment

Date

2022-12-02

Authors

Chen, Zhao, Ph. D. in cell and molecular biology

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Abstract

Glioblastoma multiforme (GBM) is the most lethal and common type of malignant brain tumor in adults. To date, no curative treatment exists for GBM despite continuous research efforts. Like many other cancers, GBM requires higher levels of methionine for survival compared with normal cells. We aim to exploit GBM methionine dependency as a therapeutic target for this lethal cancer. Our results showed that methionine depletion with an engineered human methionine-γ-lyase (hMGL) reduced GBM cell survival in vitro. Metabolic profiling and MSEA revealed that aminoacyl tRNA biosynthesis, glutathione metabolism, and nucleotide metabolism were significantly changed by hMGL treatment. Mechanistic study showed hMGL treatment resulted in notable increases in oxidative stress in GBM cell lines, leading to DNA damage, and caused cell cycle arrest at the S/G2 phase. In line with this, thioredoxin reductase inhibitor, auranofin, and ATR inhibitor, ceralasertib, showed synergistic effects with hMGL in inhibiting GBM cells. Furthermore, hMGL treatment caused a decrease of global DNA methylation and altered histone methylation patterns. This upregulated the expression of tumor-suppressive microRNAs miR-124 and miR-137, which are frequently silenced in gliomagenesis due to aberrant DNA methylation. Accordingly, hMGL inhibited the phosphorylation and activation of their downstream target, STAT3, a central mediator of GBM growth. Finally, hMGL inhibited the growth of orthotopic human GBM xenografts in vivo and prolonged survival time of tumor-bearing animals. Our data provides strong rationale to investigate the efficacy of hMGL in the treatment for GBM.

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