Selective Cytotoxicity of the NAMPT Inhibitor FK866 Toward Gastric Cancer Cells With Markers of the Epithelial-Mesenchymal Transition, Due to Loss of NAPRT

Lee, Jooyoung; Kim, Hyosil; Lee, Jae Eun; Shin, Su‐Jin; Oh, Sejin; Kwon, Gino; Kim, Hakhyun; Choi, Yoon Young; White, Michael A.; Paik, Soonmyung; Cheong, Jae‐Ho

doi:10.1053/j.gastro.2018.05.024

Cited by 98 publications

(101 citation statements)

References 54 publications

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“…FK866 has antineoplastic and antiangiogenic properties and induces cell death by energy depletion of metabolically active hepatocarcinoma, chronic lymphoblastic leukaemia, lymphoma and melanoma cells without affecting normal cells . In most of these studies, FK866 was administered in mice intraperitoneally without any effect on body weight and food intake despite observable decreases in NMN or NAD + in the whole brain . Studies that utilized FK866 centrally in rodents focused more on the benefits of NAMPT inhibition on neuronal injury and neuroinflammation during ischaemia without reporting effects on food intake .…”

Section: Discussionmentioning

confidence: 99%

Fasting‐ and ghrelin‐induced food intake is regulated by NAMPT in the hypothalamus

et al. 2020

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Aim Neurons in the arcuate nucleus of the hypothalamus are involved in regulation of food intake and energy expenditure, and dysregulation of signalling in these neurons promotes development of obesity. The role of the rate‐limiting enzyme in the NAD+ salvage pathway, nicotinamide phosphoribosyltransferase (NAMPT), for regulation energy homeostasis by the hypothalamus has not been extensively studied. Methods We determined whether Nampt mRNA or protein levels in the hypothalamus of mice were affected by diet‐induced obesity, by fasting and re‐feeding, and by leptin and ghrelin treatment. Primary hypothalamic neurons were treated with FK866, a selective inhibitor of NAMPT, or rAAV carrying shRNA directed against Nampt, and levels of reactive oxygen species (ROS) and mitochondrial respiration were assessed. Fasting and ghrelin‐induced food intake was measured in mice in metabolic cages after intracerebroventricular (ICV)‐mediated FK866 administration. Results NAMPT levels in the hypothalamus were elevated by administration of ghrelin and leptin. In diet‐induced obese mice, both protein and mRNA levels of NAMPT decreased in the hypothalamus. NAMPT inhibition in primary hypothalamic neurons significantly reduced levels of NAD+, increased levels of ROS, and affected the expression of Agrp, Pomc and genes related to mitochondrial function. Finally, ICV‐induced NAMPT inhibition by FK866 did not cause malaise or anhedonia, but completely ablated fasting‐ and ghrelin‐induced increases in food intake. Conclusion Our findings indicate that regulation of NAMPT levels in hypothalamic neurons is important for the control of fasting‐ and ghrelin‐induced food intake.

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Section: Discussionmentioning

confidence: 99%

Fasting‐ and ghrelin‐induced food intake is regulated by NAMPT in the hypothalamus

et al. 2020

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“…Thus, EMT-associated molecular targets that govern chemoresistance [27,37,63] or metastatic potential [35,36] have been extensively studied for the development of novel anti-cancer therapies [64]. As such, the induction of the selective death of mesenchymal-type cancer cells using small molecules identified via library screening [65] or in silico gene signature-based analysis [9] has been highlighted as an effective potential strategy.…”

Section: Discussionmentioning

confidence: 99%

Systematic identification of a nuclear receptor-enriched predictive signature for erastin-induced ferroptosis

Kwon

Kong

Choi

et al. 2020

Preprint

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Erastin, which has been initially identified as a synthetic lethal compound against cancer expressing an RAS oncogene, inhibits cystine/glutamate antiporters and causes ferroptic cell death in various cell types, including therapy-resistant mesenchymal cancer cells. However, despite recent emerging evidence for the mechanisms underlying ferroptosis, molecular biomarkers associated with erastin-dependent ferroptosis have not yet been identified. In the present study, we employed isogenic lung cancer cell models with therapyresistant mesenchymal properties to show that a redox imbalance leads to glutathione depletion and ferroptotic cell death. Subsequent gene expression analysis of pan-cancer cell lines revealed that the activity of transcription factors, including nuclear factor erythroid 2related factor 2 (NRF2) and aryl hydrocarbon receptor (AhR), serve as important markers of erastin resistance. Based on the integrated expression of genes in the nuclear receptor metapathway (NRM), we constructed an NRM model and validated its robustness using an independent pharmacogenomics dataset. The NRM model was further evaluated by employing it in the sensitivity testing of nine cancer cell lines for which erastin sensitivitieshad not yet been undetermined. Our pharmacogenomics approach has the potential to pave the way for the efficient classification of patients for therapeutic intervention using erastin or erastin analogs.

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“…50 Of note, Kuboki et al 44 and nicotinamide phosphoribosyltransferase (NAMPT) inhibitors in the ACRG EMT subtype. 52 These findings, subject to further validation, are especially exciting for the future of precision oncology, given the significant progress made recently in the development of patient-derived organoids as drug-testing platforms, which have shown the potential to recapitulate and predict in vivo patient clinical responses. 53,54 Converging evidence appears to suggest the presence of "immunogenic" tumor subtypes which benefit most from immunotherapy.…”

Section: From B En Ch To B Eds Ide: Tr An S L Ati Onal and Clini C mentioning

confidence: 99%

“…A thorough understanding of the biological mechanisms underlying oncogenic alterations are likely to reveal further therapeutic opportunities, such as the synergistic effect of SHP2 and MEK2 inhibition in KRAS‐amplified GC . Previously discussed molecular classifications also hold implications for targeted therapies, exposing potential vulnerabilities such as PI3K/AKT/mTOR inhibitors in the Lei et al mesenchymal subtype, insulin‐like growth factor 1/insulin‐like growth factor 1 receptor (IGF1/IGF1R) inhibitors in the Oh et al MP subtype and nicotinamide phosphoribosyltransferase (NAMPT) inhibitors in the ACRG EMT subtype . These findings, subject to further validation, are especially exciting for the future of precision oncology, given the significant progress made recently in the development of patient‐derived organoids as drug‐testing platforms, which have shown the potential to recapitulate and predict in vivo patient clinical responses …”

Section: From Bench To Bedside: Translational and Clinical Utility Ofmentioning

confidence: 99%

Dissection of gastric cancer heterogeneity for precision oncology

Tan

2019

Cancer Science

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Gastric cancer (GC) remains the fifth most prevalent cancer worldwide and the third leading cause of global cancer mortality. Comprehensive ‐omic studies have unveiled a heterogeneous GC landscape, with considerable molecular diversity both between and within tumors. Given the complex nature of GC, a long‐sought goal includes effective identification of distinct patient subsets with prognostic and/or predictive outcomes to enable tailoring of specific treatments (“precision oncology”). In this review, we highlight various approaches to molecular classification in GC, covering recent genomic, transcriptomic, proteomic and epigenomic features. We pay special attention to the translational significance of classifier systems and examine potential confounding factors which deserve further investigation. In particular, we discuss recent advancements in our knowledge of intra‐subtype, intra‐patient and intra‐tumor heterogeneity, and the pivotal role of the tumor stromal microenvironment.

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Selective Cytotoxicity of the NAMPT Inhibitor FK866 Toward Gastric Cancer Cells With Markers of the Epithelial-Mesenchymal Transition, Due to Loss of NAPRT

Cited by 98 publications

References 54 publications

Fasting‐ and ghrelin‐induced food intake is regulated by NAMPT in the hypothalamus

Fasting‐ and ghrelin‐induced food intake is regulated by NAMPT in the hypothalamus

Systematic identification of a nuclear receptor-enriched predictive signature for erastin-induced ferroptosis

Dissection of gastric cancer heterogeneity for precision oncology

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