Induction of Ferroptosis by Ophiopogonin-B Through Regulating the Gene Signature AURKA in NSCLC

Li, Liqiu; Gao, Qian; Wang, Jin; Gu, Ling; Li, Zhihui; Zhang, Shiping; Hu, Cheng; He, Menglin; Wang, Yulin; Wang, Zixuan; Yue, Yi; Fu, Jin; Zhang, Xiongfei; Ge, Fei; Chen, Meijuan; Zhang, Xu

doi:10.3389/fonc.2022.833814

Cited by 15 publications

(8 citation statements)

References 51 publications

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“…2C), dorsomorphin (36) (AMPK inhibitor, Supplemental Fig. 2D), alisertib (37, 38) (Aurora kinase A inhibitor, Supplemental Fig. 2E), verdinexor and leptomycin B (39) (XPO1/CRM1 inhibitors, Supplemental Fig.…”

Section: Resultsmentioning

confidence: 99%

NINJ1 regulates ferroptosis via xCT antiporter interaction and CoA modulation

Chen,

Lin,

et al. 2024

Preprint

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Ninjurin-1 (NINJ1), initially identified as a stress-induced protein in neurons, recently emerged as a key mediator of plasma membrane rupture during apoptosis, necrosis, and pyroptosis. However, its involvement in ferroptosis remains unknown. Here, we demonstrate that NINJ1 also plays a crucial role in ferroptosis, but through a distinct mechanism. NINJ1 knockdown significantly protected cancer cells against ferroptosis induced by xCT inhibitors but no other classes of ferroptosis-inducing compounds (FINs). Glycine, known to inhibit canonical NINJ1-mediated membrane rupture in other cell deaths, had no impact on ferroptosis. A compound screen revealed that NINJ1-mediated ferroptosis protection can be abolished by pantothenate kinase inhibitor (PANKi), buthionine sulfoximine (BSO), and diethylmaleate (DEM). These results suggest that this ferroptosis protection is mediated via Coenzyme A (CoA) and glutathione (GSH), both of which were found to be elevated upon NINJ1 knockdown. Furthermore, we discovered that NINJ1 interacts with the xCT antiporter, which is responsible for cystine uptake for the biosynthesis of CoA and GSH. The removal of NINJ1 increased xCT levels and stability, enhanced cystine uptake, and contributed to elevated CoA and GSH levels, collectively contributing to ferroptosis protection. These findings reveal that NINJ1 regulates ferroptosis via a non-canonical mechanism, distinct from other regulated cell deaths.

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Section: Resultsmentioning

confidence: 99%

NINJ1 regulates ferroptosis via xCT antiporter interaction and CoA modulation

Chen,

Lin,

et al. 2024

Preprint

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“…However, there are few studies on the ferroptosis role and mechanism of AURKA. Li et al revealed that AURKA was a negative regulator for ferroptosis in NSCLC [ 36 ]. Zhao et al demonstrated that AURKA was a ferroptosis-related gene associated with worse survival outcomes in ES [ 37 ], but they did not further explore the specific mechanisms by which AURKA regulated ferroptosis in ES.…”

Section: Discussionmentioning

confidence: 99%

AURKA inhibition induces Ewing’s sarcoma apoptosis and ferroptosis through NPM1/YAP1 axis

Chen,

Hu,

Xiong

et al. 2024

Cell Death Dis

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Ewing’s sarcoma (ES) is a rare and highly aggressive malignant tumor arising from bone and soft tissue. Suffering from intractable or recurrent diseases, the patients’ therapy options are very limited. It is extremely urgent to identify novel potential therapeutic targets for ES and put them into use in clinical settings. In the present study, high-throughput screening of a small molecular pharmacy library was performed. The killing effect of the Aurora kinase A (AURKA) inhibitor TCS7010 in ES cells was identified, and AURKA was selected as the research object for further study. Disparate suppressants were adopted to study the cell death manner of TCS7010. TCS7010 and RNA silencing were used to evaluate the functions of AURKA in the apoptosis and ferroptosis of ES cells. Co-immunoprecipitation assay was used to investigate the correlation of AURKA and nucleophosmin1 (NPM1) in ES. Nude-mice transplanted tumor model was used for investigating the role of AURKA in ES in vivo. Investigations into the protein activities of AURKA were conducted using ES cell lines and xenograft models. AURKA was found to be prominently upregulated in ES. The AURKA expression level was remarkably connected to ES patients’ shorter overall survival (OS) and event-free survival (EFS). Furthermore, AURKA inhibition markedly induced the apoptosis and ferroptosis of ES cells and attenuated tumorigenesis in vivo. On the part of potential mechanisms, it was found that AURKA inhibition triggered the apoptosis and ferroptosis of ES cells through the NPM1/Yes1 associated transcriptional regulator (YAP1) axis, which provides new insights into the tumorigenesis of ES. AURKA may be a prospective target for clinical intervention in ES patients.

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“…Very recently, Li et al ( 2022c ) conducted a bioinformatic analysis aimed at identifying ferroptosis-related genes and prognosis in NSCLC patients. The study brought to light a 12-gene signature where AURKA , the Aurora kinase A encoding gene, was reported to act as a negative regulator of ferroptosis.…”

Section: Natural Compounds As Ferroptosis Inducersmentioning

confidence: 99%

Novel Insights on Ferroptosis Modulation as Potential Strategy for Cancer Treatment: When Nature Kills

Consoli

Fallica

Sorrenti

et al. 2024

Antioxidants & Redox Signaling

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Significance: The multifactorial nature of the mechanisms implicated in cancer development still represents a major issue for the success of established antitumor therapies. The discovery of ferroptosis, a novel form of programmed cell death distinct from apoptosis, along with the identification of the molecular pathways activated during its execution, has led to the uncovering of novel molecules characterized by ferroptosis-inducing properties. Recent advances: As of today, the ferroptosis-inducing properties of compounds derived from natural sources have been investigated and interesting findings have been reported both in vitro and in vivo . Critical Issues: Despite the efforts made so far, only a limited number of synthetic compounds have been identified as ferroptosis inducers, and their utilization is still limited to basic research. In this review, we analyzed the most important biochemical pathways involved in ferroptosis execution, with particular attention to the newest literature findings on canonical and non-canonical hallmarks, together with mechanisms of action of natural compounds identified as novel ferroptosis inducers. Compounds have been classified based on their chemical structure, and modulation of ferroptosis-related biochemical pathways has been reported. Future Directions: The outcomes herein collected represent a fascinating starting point from which to take hints for future drug discovery studies aimed at identifying ferroptosis-inducing natural compounds for anticancer therapies. Antioxid. Redox Signal. 40, 40–85.

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Induction of Ferroptosis by Ophiopogonin-B Through Regulating the Gene Signature AURKA in NSCLC

Cited by 15 publications

References 51 publications

NINJ1 regulates ferroptosis via xCT antiporter interaction and CoA modulation

NINJ1 regulates ferroptosis via xCT antiporter interaction and CoA modulation

AURKA inhibition induces Ewing’s sarcoma apoptosis and ferroptosis through NPM1/YAP1 axis

Novel Insights on Ferroptosis Modulation as Potential Strategy for Cancer Treatment: When Nature Kills

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