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NRF2 translation block by inhibition of cap-dependent initiation sensitizes lymphoma cells to ferroptosis and CAR-T immunotherapy

ABSTRACT: Cancers coopt stress-response pathways to drive oncogenesis, dodge immune surveillance, and resist cytotoxic therapies. Several of these provide protection from ferroptosis, iron-mediated oxidative cell death. Here, we found dramatic sensitization to ferroptosis upon disruption of cap-dependent translation in diffuse large B-cell lymphoma (DLBCL). Specifically, rocaglate inhibitors of the eIF4A1 RNA helicase synergized with pharmacologic ferroptosis inducers, driven by a collapse of glutathione production that protects polyunsaturated fatty acids from ferroptotic oxidation. These effects occur despite initial up-regulation of specific protective factors. We find lost translation of NRF2, oncogenic master regulator of antioxidant gene-expression, is a key consequence of eIF4A1 inhibition. In vivo, combination of the clinical rocaglate zotatifin with a pharmacologically optimized ferroptosis inducer eradicated DLBCL patient derived xenografts. Moreover, we found zotatifin pre-exposure sensitized DLBCL to CD19-directed chimeric antigen receptor (CAR-19) T cells. Translational disruption therefore provides new opportunities to leverage therapeutic impacts of ferroptosis inducers including cytotoxic immunotherapies.

ORGANISM(S): Homo sapiens

PROVIDER: GSE277298 | GEO | 2025/06/02

REPOSITORIES: GEO

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NRF2 translation block by inhibition of cap-dependent initiation sensitizes lymphoma cells to ferroptosis and CAR-T immunotherapy

Project description:Cancers coopt stress-response pathways to drive oncogenesis, dodge immune surveillance, and resist cytotoxic therapies. Several of these provide protection from ferroptosis, iron-mediated oxidative cell death. Here, we found dramatic sensitization to ferroptosis upon disruption of cap-dependent translation in diffuse large B-cell lymphoma (DLBCL). Specifically, rocaglate inhibitors of the eIF4A1 RNA helicase synergized with pharmacologic ferroptosis inducers, driven by a collapse of glutathione production that protects polyunsaturated fatty acids from ferroptotic oxidation. These effects occur despite initial up-regulation of specific protective factors. We find lost translation of NRF2, oncogenic master regulator of antioxidant gene-expression, is a key consequence of eIF4A1 inhibition. In vivo, combination of the clinical rocaglate zotatifin with a pharmacologically optimized ferroptosis inducer eradicated DLBCL patient derived xenografts. Moreover, we found zotatifin pre-exposure sensitized DLBCL to CD19-directed chimeric antigen receptor (CAR-19) T cells. Translational disruption therefore provides new opportunities to leverage therapeutic impacts of ferroptosis inducers including cytotoxic immunotherapies.

2025-04-03 | PXD055896 | Pride

PAR-CLIP analysis of neuroblastoma cells in response to amidino-rocaglate treatment

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BRD4 inhibition sensitizes diffuse large B-cell lymphoma cells to ferroptosis

Project description:Diffuse large B-cell lymphoma (DLBCL), the most common form of non-Hodgkin lymphoma, is characterized by an aggressive clinical course. In approximately one-third of DLBCL patients, first-line multi-agent immunochemotherapy fails to produce a durable response. Molecular heterogeneity and apoptosis resistance pose major therapeutic challenges in DLBCL treatment. To circumvent apoptosis resistance, the induction of ferroptosis might represent a promising strategy for lymphoma therapy. Here, a compound library targeting epigenetic modulators was screened to identify ferroptosis-sensitizing drugs. Strikingly, bromodomain and extra-terminal domain (BET) inhibitors sensitized cells of the germinal center B cell-like (GCB) subtype of DLBCL to ferroptosis induction and the combination of BET inhibitors with ferroptosis inducers, such as dimethyl fumarate (DMF) or RSL3, synergized in the killing of DLBCL cells in vitro and in vivo. On the molecular level, the BET protein BRD4 was found to be an essential regulator of ferroptosis suppressor protein 1 (FSP1) expression and to thus protect GCB DLBCL cells from ferroptosis. Collectively, we identified and characterized BRD4 as an important player in ferroptosis suppression in GCB DLBCL and provide a rationale for the combination of BET inhibitors with ferroptosis-inducing agents as a novel therapeutic approach for DLBCL treatment.

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Authentication of Hippuristanol-eIF4A1 Target Engagement Facilitates Identification of eIF4A1 Helicase Dependencies within 5’ Leader Regions

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2020-08-05 | GSE151687 | GEO

Selective translation mechanism through two paralogs of eukaryotic initiation factor 4A

Project description:Eukaryotic initiation factor (eIF) 4A is a DEAD-box RNA-binding protein that plays a pivotal role in translation initiation. Although mammals have two eIF4A paralogs, eIF4A1 and eIF4A2, their redundancy has been long assumed because of high homology and their functional difference has been poorly understood. Here we show that eIF4A paralogs employ differential translation programs. Ribosome profiling of eIF4A1- and eIF4A2-knockout HEK293T cell lines revealed that translation efficiency changes were divergent across transcriptome and distinct group of mRNAs were regulated by each paralog. Our analysis indicates that eIF4A1 and eIF4A2 facilitate translation of specific mRNAs.

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eIF4A1 enhances LARP1-mediated translational repression during mTORC1 inhibition

Project description:Eukaryotic translation initiation factor (eIF) 4A — a DEAD-box RNA-binding protein — plays an essential role in translation initiation. Recent reports have suggested helicase-dependent and helicase-independent functions for eIF4A, but the multifaceted roles of eIF4A have not been fully explored. Here, we show that eIF4A1 enhances translational repression during the inhibition of mechanistic target of rapamycin complex 1 (mTORC1), an essential kinase complex controlling cell proliferation. RNA pulldown followed by sequencing revealed that eIF4A1 preferentially binds to mRNAs containing terminal oligopyrimidine (TOP) motifs (TOP mRNAs), whose translation is rapidly repressed upon mTORC1 inhibition. This selective interaction depends on a La-related RNA-binding protein, LARP1. Ribosome profiling revealed that deletion of EIF4A1 attenuated the translational repression of TOP mRNAs upon mTORC1 inactivation. Moreover, eIF4A1 increases the affinity between TOP mRNAs and LARP1 and thus ensures stronger translational repression upon mTORC1 inhibition. Our data show the multimodality of eIF4A1 in modulating protein synthesis through an inhibitory binding partner and provide a unique example of the repressive role of a universal translational activator.

2024-02-13 | GSE184247 | GEO

HDAC inhibitors sensitize colorectal cancer to ferroptosis via m6A modification of FSP1

Project description:Ferroptosis therapy has been well-established in various cancers; however, colorectal cancer (CRC) is highly resistant to ferroptosis, which hinders the use of ferroptosis therapy in CRC. Through drug screening, we found histone deacetylase inhibitor (HDACi) significantly sensitized ferroptosis. Mechanically, HDACi reduced FSP1 by promoting its mRNA degradation, a known ferroptosis defense molecular. In further research, we confirmed that HDACi specifically targeted HDAC1 and suppressed the H3K27ac modification of FTO and ALKBH5. The activation of FTO and ALKBH5 resulted in a reduction of N6-methyladenosine (m6A) modification on FSP1 mRNA, leading to its degradation and ultimately sensitizing CRC to ferroptosis. The combination of HDACi and ferroptosis inducers synergically reduced CRC both in vivo and in vitro. In conclusion, our research reveals how HDACi sensitized ferroptosis and prompts the combination of HDACi/ferroptosis inducers as a promising therapeutic strategy for solid tumors.

2025-04-03 | GSE263463 | GEO

RNA seq data of sorafenib resistant HepG2 cells

Project description:To investigate the molecular mechanism of ferroptosis resistance in HCC, we applied sorafenib, one of the class I ferroptosis inducers (FINs), to generate HepG2 sorafenib resistant (SR) cells.

2024-02-03 | GSE248764 | GEO

Translatome and Translation Machinery Remodeling by eIF4A Inhibitors Mediates Antitumor Potency.

Project description:Protein synthesis-targeting agents against eIF4A activity, including rocaglates, are actively pursued as anticancer and antiviral therapies. Yet, their full effect on the translational landscape is unknown, especially with regards to up-regulated proteins and drug-activated translation factors that mediate rocaglates’ remarkable anticancer potency. Here, we investigated rocaglate-driven global translational remodeling in cancer cells. Proteomic translatome analysis by TMT-pulse-SILAC revealed an extensive repertoire of rocaglate-inducible proteins that regulate hitherto unrecognized mechanisms of cytotoxicity. As proof-of-concept, we show that GEF-H1 induction activates anti-survival RHOA/JNK signaling. Intriguingly, rocaglate responses persist in eIF4A-depleted cells. Global MATRIX survey of translation machinery adaptations to rocaglates revealed augmented translational activities of the general translation factor eEF1ε1, and the DEAD-box RNA helicase DDX17, which drive rocaglate-specific protein induction and drug response. This original unbiased proteomic interrogation of rocaglate-driven translational reprogramming transforms the current definition of rocaglates as one-dimensional eIF4A inhibitors to comprehensive remodelers of the protein synthesis landscape.

2021-11-23 | PXD022556 | Pride

EIF4A1 is essential in B cells by promoting activation-induced translation

Project description:EIF4A1 and cofactors EIF4B and EIF4H have been well characterised in cancers, including B cell malignancies, for their ability to promote the translation of oncogenes with structured 5’ untranslated regions but very little is known of their roles in non-malignant cells. Using mouse models to delete Eif4a1, Eif4b or Eif4h in B cells we show that EIF4A1, but not EIF4B or EIF4H, is essential for B cell development and the germinal centre response. Following activation, EIF4A1 facilitates an increased rate of protein synthesis, MYC expression and expression of cell cycle regulators. However, EIF4A1-deficient cells remain viable whereas Hippuristanol treatment induces cell death.

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