Deferasirox induces cyclin D1 degradation and apoptosis in mantle cell lymphoma in a reactive oxygen species‐ and GSK3β‐dependent mechanism

Abstract

Summary Mantle cell lymphoma (MCL) is a difficult‐to‐treat B‐cell malignancy characterized by cyclin D1 (CD1) overexpression. Targeting CD1 in MCL has been shown to be of therapeutic significance. However, treatment of MCL remains challenging since patients are still subject to early and frequent relapse of the disease. To ensure their high proliferation rate, tumour cells have increased iron needs, making them more susceptible to iron deprivation. Indeed, several iron chelators proved to be effective anti‐cancer agents. In this study, we demonstrate that the clinically approved iron chelator deferasirox (DFX) exerts an anti‐tumoural effect in MCL cell lines and patient cells. The exposure of MCL cells to clinically feasible concentrations of DFX resulted in growth inhibition, cell cycle arrest and induction of apoptosis. We show that DFX unfolds its cytotoxic effect by a rapid induction of reactive oxygen species (ROS) that leads to oxidative stress and severe DNA damage and by triggering CD1 proteolysis in a mechanism that requires its phosphorylation on T286 by glycogen synthase kinase‐3β (GSK3β). Moreover, we demonstrate that DFX mediates CD1 proteolysis by repressing the phosphatidylinositol 3‐kinase (PI3K)/AKT/GSK3β pathway via ROS generation. Our data suggest DFX as a potential therapeutic option for MCL and paves the way for more treatment options for these patients.

Ferrous–sucrose complex supplementation regulates maternal plasma metabolism and the fecal microbiota composition and improves neonatal immunity and placental glucose transportation by activating the EGF/PI3K/AKT signaling pathways in sows

“…30 Studies have previously demonstrated that iron deficiency inhibited PI3K-Akt signaling, while iron supplementation stimulated cell proliferation by activating PI3K/Akt signaling in different cells. 31,32 Iron supplementation increased Akt phosphorylation, while administration of the PI3K inhibitor completely blocked the iron-induced phosphorylation of Akt. 33 In the current study, maternal FeSuc supplementation was able to regulate PI3K activity by promoting the transcription of growth factors in the placenta.…”

Degradation strategy of cyclin D1 in cancer cells and the potential clinical application

“…Chelating agent: Smara et al. ( 50 ) applied iron chelator deferasirox (DFX) to mantle cell lymphoma (MCL) cells, and found that DFX lead to cyclin D1 proteolysis and degradation in a mechanism that requires its phosphorylation on T286 by glycogen synthase kinase-3β (GSK3β). Several iron chelators were proved to be effective anti-cancer agents and potential therapeutic potions, leading to the ubiquitin-proteasome degradation of cyclin D1.…”

Identifying and overcoming rituximab resistance in diffuse large B-cell lymphoma using next-generation sequencing

“…The authors also found that the orally administered iron chelator deferasirox [ 4 ] has a synergistic effect with rituximab in killing RRCL cells [ 5 ]. This suggests that activation of p38 MAPK may be a key driver of rituximab resistance and that inhibiting p38 MAPK with deferasirox may be a promising approach to re-sensitizing DLBL cells to rituximab.…”