Oxidative stress induced protein aggregation via GGCT produced pyroglutamic acid in drug resistant glioblastoma.

ABSTRACT: Drug resistance is a major barrier to cancer therapies and remains poorly understood. Recently, non-mutational mechanisms of drug resistance have been proposed where a more plastic metabolic response can play a major role. Here, we show that upon drug resistance, glioblastoma (GBM) cells have increased oxidative stress, mitochondria function, and protein aggregation. Gamma (γ)-glutamylcyclotranserase (GGCT), an enzyme in the γ-glutamyl cycle for glutathione production, located on chromosome 7 which is commonly amplified in GBM is also increased upon resistance. We further observe that the byproduct of GGCT-pyroglutamic acid-can bind aggregating proteins and that genetic and pharmacological inhibition of GGCT prevents protein aggregation. Finally, we found increased protein aggregation, GGC

SUBMITTER: Tiek D 

PROVIDER: S-EPMC11821397 | biostudies-literature | 2025 Feb

REPOSITORIES: biostudies-literature