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Inhibition of thioredoxin reductase 1 sensitizes glucose-starved glioblastoma cells to disulfidptosis 1

ABSTRACT: Disulfidptosis is a recently identified form of cell death characterized by the aberrant accumulation of cellular disulfides. This process primarily occurs in glucose-starved cells expressing higher levels of SLC7A11 and has been proposed as a therapeutic target for cancers with hyperactive SCL7A11. However, the potential for inducing disulfidptosis through other mechanisms in cancers remains unclear. Here, we found that inhibiting thioredoxin reductase 1 (TrxR1), a key enzyme in the thioredoxin system, induces disulfidptosis in glioblastoma (GBM) cells. TrxR1 expression is elevated in GBM with activated transcriptional coactivator with PDZ-binding motif (TAZ) and correlates with poor prognosis. TrxR1 inhibitors induced GBM cell death that can be rescued by disulfide reducers but not by ROS scavengers or inhibitors of apoptosis, ferroptosis, or necroptosis. Glucose-starved cells, but not those deprived of oxygen or glutamine, increased TrxR1 expression in an NRF2-dependent manner and were more sensitive to TrxR1 inhibition-induced cell death. The dying cells initially exhibited highly dynamic lamellipodia, followed by actin cytoskeleton collapse. This process involved the accumulation of cytosolic peroxisomes and micropinocytic caveolae, as well as small gaps in the plasma membrane. Depletion of the WAVE complex component NCKAP1 partially rescued the cells, whereas Rac inhibition enhanced cell death. In an orthotopic xenograft GBM mouse model, TrxR1 depletion inhibited tumor growth and improved survival. Furthermore, cells undergoing TrxR1 inhibition exhibited features of immunogenic cell death. Therefore, this study suggests the potential of targeting TrxR1 as a therapeutic strategy in GBM.

ORGANISM(S): Homo sapiens

PROVIDER: GSE282324 | GEO | 2024/12/23

REPOSITORIES: GEO

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Project description:Glioblastoma (GBM) carries a dismal prognosis largely due to acquired resistance to the standard treatment, which incorporates the chemotherapy temozolomide (TMZ). Inhibiting the proteasomal pathway is an emerging strategy, where combination treatments are under clinical investigation. We hypothesized that pre-treatment of GBM with bortezomib (BTZ) might sensitize glioblastoma to TMZ by abolishing autophagy survival signals to augment DNA damage and apoptosis. P3 patient-derived GBM cells as well as the tumor cell lines U87, HF66, A172 and T98G were investigated for clonogenic survival after single or combined treatment with TMZ and BTZ in vitro. Change in autophagic flux was examined after experimental treatments in conjunction with inhibitors of autophagy or downregulation of autophagy-related genes -5 and -7 (ATG5 and ATG7, respectively). Autophagic flux was increased in TMZ-resistant P3 and T98G cells as indicated by diminished levels of the autophagy markers LC3A/B-II and increased STX17, higher protein degradation and no formation of p62 bodies nor induction of apoptosis. In contrast, BTZ treatment attenuated ULK1 mRNA, total and phosphorylated protein, and accumulated LC3A/B-II, p62 and autophagosomes analogously to Baf1 and chloroquine autophagy inhibitors. These autophagosomes did not fuse with lysosomes, indicated by attenuated STX17 expression and reduced degradation of long-lived proteins, which culminated in enhanced caspase-3/8 dependent apoptosis. BTZ synergistically enhanced TMZ efficacy, attenuated tumor cell proliferation, triggered ATM/Chk2 DNA damage signalling to further augment caspase-3/8 mediated apoptosis in the TMZ resistant P3 and T98G GBM cells. Genetic or chemical inhibition of autophagy (with CRISPR-CAs9 ATG5, ATG7 shRNA, MRT68921 or VPS34-IN1) abrogated BTZ efficacy and rescued BTZ+ TMZ treated GBM cells from death. We conclude that Bortezomib ameliorates temozolomide resistance through ATG5/7-dependent abrogated autophagic flux and may be amenable in combination treatment regimens for TMZ refractory GBM patients.

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Inhibition of thioredoxin reductase 1 sensitizes glucose-starved glioblastoma cells to disulfidptosis 1

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