ABSTRACT
GLS1 orchestrates glutaminolysis and promotes cell proliferation when glutamine is abundant by regenerating TCA cycle intermediates and supporting redox homeostasis. CB-839, an inhibitor of GLS1, is currently under clinical investigation for a variety of cancer types. Here, we show that GLS1 facilitates apoptosis when glutamine is deprived. Mechanistically, the absence of exogenous glutamine sufficiently reduces glutamate levels to convert dimeric GLS1 to a self-assembled, extremely low-Km filamentous polymer. GLS1 filaments possess an enhanced catalytic activity, which further depletes intracellular glutamine. Functionally, filamentous GLS1-dependent glutamine scarcity leads to inadequate synthesis of asparagine and mitogenome-encoded proteins, resulting in ROS-induced apoptosis that can be rescued by asparagine supplementation. Physiologically, we observed GLS1 filaments in solid tumors and validated the tumor-suppressive role of constitutively active, filamentous GLS1 mutants K320A and S482C in xenograft models. Our results change our understanding of GLS1 in cancer metabolism and suggest the therapeutic potential of promoting GLS1 filament formation.
Subject(s)
Glutaminase , Glutamine , Apoptosis , Asparagine/genetics , Glutaminase/genetics , Glutaminase/metabolism , Glutamine/metabolism , Humans , Reactive Oxygen SpeciesABSTRACT
Curcumin, an active ingredient from the rhizome of the plant, Curcuma longa, has antioxidant, anti-inflammatory and anti-cancer activities. It has recently been demonstrated that the chemopreventive activities of curcumin might be due to its ability to inhibit cell growth and induce apoptosis. In the present study, we have investigated the effects of curcumin on growth and apoptosis in the human ovarian cancer cell line Ho-8910 by MTT assay, fluorescence microscopy, flow cytometry and Western blotting. Our data revealed that curcumin could significantly inhibit the growth and induce apoptosis in Ho-8910 cells. A decrease in expression of Bcl-2, Bcl-X(L) and pro-caspase-3 was observed after exposure to 40 microM curcumin, while the levels of p53 and Bax were increased in the curcumin-treated cells. These activities may contribute to the anticarcinogenic action of curcumin.