Targeting STK17B kinase activates ferroptosis and suppresses drug resistance in multiple myeloma
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ABSTRACT:
PROVIDER: PRJNA1320666 | ENA |
REPOSITORIES: ENA
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Project description:The progression of multiple myeloma (MM), an incurable malignancy of plasma cells, is oftenassociated with the suppression of ferroptosis, a type of cell death driven by iron-dependent lipid peroxidation. The mechanisms underlying this suppression remain largely unknown. Here, we identified STK17B kinase as a critical suppressor of ferroptosis in MM. Elevated levels of STK17B are associated with poor overall survival in MM patients and STK17B expression is significantly higher in relapsed vs newly diagnosed MM cases. We found that inhibiting STK17B in MM cells increased the labile iron pool, enhanced lipid peroxidation, and sensitized cells to conventional anti-MM therapies. Notably, an orally available, in-house-generated STK17B inhibitor induced ferroptosis and significantly reduced tumor growth in MM xenograft mouse models. Mechanistically, proximity labeling assay combined with the phospho-proteomic analysis identified two major regulators of iron uptake and transport as direct targets of STK17B: iron-responsive element binding protein 2 (IREB2) and heat shock protein family B member 1 (HSPB1). We demonstrated that STK17B phosphorylates critical regulatory sites on IREB2 (S157) and HSPB1 (S15), thereby modulating the balance between IREB2 and HSPB1 downstream effectors, pro-ferroptotic transferrin receptor and anti-ferroptotic ferritin heavy chain proteins. Furthermore, we demonstrated that STK17B indirectly maintains activating phosphorylation of STAT3, a ferroptosis suppressor and a major driver of MM pathobiology. Our findings uncovered a clinically relevant and targetable STK17B-pIREB2S157/pHSPB1S15 signaling axis that suppresses ferroptosis and contributes to drug resistance in MM.
2025-09-05 | GSE307399 | GEO
Project description:During metastasis, cancer cells face significant survival pressures, including treatment-induced ferroptosis. Adaptation to ferroptosis stress orchestrates the metastasis of colorectal cancer (CRC) cells. However, the reciprocal regulatory mechanisms of ferroptosis and metastasis remain unknown. Here, through a CRISPR–Cas9 screen, we discovered that N-acetylneuraminate synthase (NANS) is a positive regulator of ferroptosis in CRC, regardless of its metabolic function. Moreover, NANS expression is downregulated and is clinically associated with poor prognosis in CRC patients. In a ferroptotic stress environment, NANS is phosphorylated by cyclin-dependent kinase 1 (CDK1) at serine 275 (S275), and phosphorylated NANS (NANS pS275) dissociates from TAK1 and is subsequently ubiquitinated by the E3 ligase ubiquitin-conjugating enzyme E2 N (UBE2N) at lysine 246 (K246) for degradation, which further activates TAK1 and nuclear factor κB (NF-κB) signaling and the expression of the ferroptosis negative regulatory factor FTH1, resulting in ferroptosis resistance and finally promoting metastasis. Furthermore, the NANS pS275 intensity is correlated with the degree of malignancy and the prognosis of CRC patients. Our study revealed that NANS inhibits CRC metastasis by promoting ferroptosis and that the CDK1-mediated phosphorylation of NANS at S275 may guide the utilization of chemical compounds to promote ferroptosis and thus block CRC metastasis.
2025-05-08 | PXD062501 | Pride
Project description:Ferroptosis is a unique iron-dependent form of non-apoptotic cell death characterized by devastating lipid peroxidation. Whilst growing evidence suggests that ferroptosis is a type of autophagy-dependent cell death, the underlying molecular mechanisms regulating ferroptosis are largely unknown. In this study, through an unbiased RNA-sequencing screening, we demonstrate the activation of a multi-faceted tumor-suppressor protein Par-4/PAWR during ferroptosis. Functional studies reveal that genetic depletion of Par-4 effectively blocks ferroptosis, whereas Par-4 overexpression sensitizes cells to undergo ferroptosis. More importantly, we have determined that Par-4-triggered ferroptosis is mechanistically driven by the autophagic machinery. Upregulation of Par-4 promotes activation of ferritinophagy (autophagic degradation of ferritin) via the nuclear receptor co-activator 4 (NCOA4), resulting in excessive release of free labile iron and, hence, enhanced lipid peroxidation and ferroptosis. Inhibition of Par-4 dramatically suppresses the NCOA4-mediated ferritinophagy signaling axis. Our results also establish that Par-4 activation positively correlates with reactive oxygen species (ROS) production, which is critical for ferritinophagy-mediated ferroptosis. Furthermore, Par-4 knockdown effectively blocked ferroptosis-mediated tumor suppression in the mouse xenograft models. Collectively, these findings reveal that Par-4 has a crucial role in ferroptosis, which could be further exploited for cancer therapy.
2024-05-24 | GSE267823 | GEO
Project description:Acquired and primary therapy resistance remain a major hurdle in clinical treatment of multiple myeloma (MM). Despite the availability of broad spectrum anti-cancer drugs, most MM patients eventually relapse and become refractory to current treatments. Therefore, we explored whether therapy-resistant MM cells are sensitive to ferroptosis induction, an iron-catalyzed mode of cell death associated with increased lipid peroxidation. In this study, we exposed glucocorticoid-resistant MM1R and glucocorticoid-sensitive MM1S cells to ferroptosis inducers RSL3 and evaluated their transcriptional changes via RNA sequencing. Compared to untreated controls, ferroptotic RSL3-treated cells displayed a significant upregulation of genes involved in inflammation, kinase signaling, cellular stress, and cell death pathways. Pre-treatment with ferroptosis inhibitor Fer-1 partly reverted these RSL3-induced transcriptional changes and revealed that especially genes involved in metal binding, nuclear receptor signaling, chromatin remodeling, and gene transcription regulation are pivotal for ferroptosis induction. Overall, these findings suggest that ferroptosis effectively targets MM1 cells and that RSL3-mediated ferroptosis triggers similar oxidative stress and cell death pathways in both MM1R and MM1S cells, irrespective of their glucocorticoid-sensitivity status.
2021-11-08 | GSE182638 | GEO
Project description:Tumor suppressor Par-4 activates autophagy-dependent ferroptosis
| PRJNA1113319 | ENA
Project description:GINS4 suppresses ferroptosis by antagonizing p53 acetylation with Snail.
2023-03-21 | PXD040993 |
Project description:Ferroptosis constitutes a promising therapeutic strategy against cancer by efficiently targeting the highly tumorigenic and treatment-resistant cancer stem cells (CSCs). We previously showed that the lysosomal iron-targeting drug Salinomycin (Sal) was able to eliminate CSCs by triggering ferroptosis. Here, in a well-established breast CSCs model (human mammary epithelial HMLER CD24low/CD44high), we identified that pharmacological inhibition of mechanistic target of rapamycin (mTOR), suppresses Sal-induced ferroptosis. Mechanistically, mTOR inhibition modulates iron cellular flux and prevents the iron and ROS bursts induced by Sal. Besides, integration of multi-omics data identified mitochondria as a key target of Sal action. We demonstrated that mTOR inhibition prevents Sal-induced mitochondrial functional and structural alteration, and that Sal-induced metabolic plasticity is mainly dependent on the mTOR pathway. Overall, our findings provide experimental evidences on the detailed mechanisms of mTOR as a crucial effector of Sal-induced ferroptosis, and gives proof-of-concept that careful evaluation of such combination therapy (here mTOR and ferroptosis co-targeting) is required for effective treatment.
2023-12-20 | PXD041545 | Pride
Project description:Ferroptosis is a form of regulated cell death that is mediated by accumulation of lipid peroxidation. Emerging evidences report dispersion of ferroptosis between neighboring cells. However, the molecular mechanism underlying the propagation of ferroptosis remains unclear. Here we provide evidences that ferroptotic cells elicit cellular projections that produce massive extracellular vesicles (EVs). Proteomic analysis reveals that these EVs are CD9 positive and contain major components of mitogen-activated protein kinase (MAPK) signaling. MAP2K1/2 that is transferred by EVs increases the sensitivity to ferroptosis of target cells. We further show that a MAP2K-interacting transcription factor, peroxisome-proliferator activator receptor gamma (PPARG), activates various components of ferroptosis defense systems. Moreover, perturbation of EV-based transport protects adjacent tissue from ferroptosis in vivo. Our study reveals an EV-dependent transport between ferroptotic cells and surrounding neighbors and establishes that MAPK-responsive PPARG is essential for ferroptosis defense in recipient cells.
2025-01-05 | GSE251770 | GEO
Project description:Circular RNAs (circRNAs) have been implicated in the tumorigenesis of non-small cell lung cancer (NSCLC). Ferroptosis is considered a mechanism to suppress tumorigenesis. Herein, we identified a novel downregulated circRNA, circPOLA2 (hsa_circ_0004291), in NSCLC tissues and found that it was correlated with advanced clinical stage in patients. Nuclear-cytoplasmic fractionation assays and FISH assays confirmed that circPOLA2 was predominantly localized in the cytoplasm. Overexpression of circPOLA2 promoted lipid peroxidation and ferroptosis in NSCLC cells, thereby inhibiting cell proliferation and migration, while knockdown of circPOLA2 exerted the opposite effects. Mechanistically, circPOLA2 interacted with Merlin, a critical regulator of the Hippo pathway, and restricted Merlin phosphorylation at S518, leading to the activation of the Hippo pathway. In addition, circPOLA2 enhanced ferroptosis in NSCLC cells by activating the Hippo pathway. Together, circPOLA2 sensitizes cells to ferroptosis and suppresses tumorigenesis in NSCLC by facilitating Merlin-mediated activation of the Hippo signaling pathway.
2024-08-20 | GSE254362 | GEO
Project description:Fanconi Anemia (FA) is a rare genetic disorder characterized by an increased susceptibility to squamous cell cancers. Fifteen FA genes are known, and the encoded proteins cooperate in a common DNA repair pathway. A critical step is the monoubiquitination of the FANCD2 protein, and cells from most FA patients are deficient in this step. How monoubiquitinated FANCD2 suppresses squamous cell cancers is unknown. Here we show that Fancd2-deficient mice are prone to Ras oncogene-driven skin carcinogenesis, while Usp1-deficient mice, expressing elevated cellular levels of Fancd2-Ub, are resistant to skin tumors. Moreover, Fancd2-Ub activates the transcription of the tumor suppressor TAp63, thereby promoting cellular senescence and blocking skin tumorigenesis. For FA patients, the reduction of FANCD2-Ub and TAp63 protein levels may account for their susceptibility to squamous cell neoplasia. Taken together, Usp1 inhibition may be a useful strategy for upregulating TAp63 and preventing or treating squamous cell cancers in the general non-FA population. Examination of FANCD2 binding after UV treatment in 293T cells
2013-06-27 | E-GEOD-46902 | biostudies-arrayexpress