N6-isopentenyladenosine induces cell death through necroptosis in human glioblastoma cells

Pagano, Cristina; Navarra, Giovanna; Coppola, Laura; Avilia, Giorgio; Pastorino, Olga; Monica, Rosa Della; Buonaiuto, Michela; Torelli, Giovanni; Caiazzo, Pasquale; Bifulco, Maurizio; Laezza, Chiara

doi:10.1038/s41420-022-00974-x

Cited by 15 publications

(16 citation statements)

References 29 publications

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“…144 Pagano et al identified a natural novel necroptosis agonist, N6-isopentenyl adenosine (iPA), which induced only necroptosis and no apoptosis in primary glioblastoma cells. 148 Following iPA treatment, higher p-RIPK1/3 and p-MLKL levels were detected, and Nec-1s was observed to rescue cells from necroptosis. Abdel-Salam et al discovered a synthetic peptide, LyeTxI-b, that engendered cytotoxicity against glioblastoma cells by primarily inducing necroptosis and, hence, was a potential novel prototypic cell model.…”

Section: Zika Virus and West Nile Virusmentioning

confidence: 97%

“…Nec-1 is reportedly the first RIPK1 inhibitor, 1 along with Nec-1s, which has been widely used in mechanism research. 64,106,148,161,167 The crystal complex of the RIPK1 kinase with Nec-1, Nec-3, and Nec-4 revealed the structural basis of necrostatin-mediated RIPK1 inhibition for precise drug design. 179 According to the binding modes, RIPK1 inhibitors can be categorized as type I, II, and III inhibitors, 180 and some of them have entered clinical trials (discussed in our recent review 181 ).…”

Section: Necroptosis Inhibitorsmentioning

confidence: 99%

“…Glioblastoma is a grade IV tumor, usually exhibiting astrocytic cell lineage, and is among the most commonly diagnosed malignant brain and other CNS tumor, with a median survival of 12–15 months and an extremely low 5-year survival rate . Pagano et al identified a natural novel necroptosis agonist, N6-isopentenyl adenosine (iPA), which induced only necroptosis and no apoptosis in primary glioblastoma cells . Following iPA treatment, higher p-RIPK1/3 and p-MLKL levels were detected, and Nec-1s was observed to rescue cells from necroptosis.…”

Section: Necroptosis In Cns Diseasesmentioning

confidence: 99%

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Role of Necroptosis in Central Nervous System Diseases

Shao

Wang

et al. 2022

ACS Chem. Neurosci.

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Necroptosis is a type of precisely regulated necrotic cell death activated in caspase-deficient conditions. Multiple factors initiate the necroptotic signaling pathway, including toll-like receptor 3/4, tumor necrosis factor (TNF), dsRNA viruses, and T cell receptors. Presently, TNF-induced necroptosis via the phosphorylation of three key proteins, receptor-interacting protein kinase 1, receptor-interacting protein kinase 3, and mixed lineage kinase domain-like protein, is the best-characterized process. Necroptosis induced by Z-DNA-binding protein 1 (ZBP-1) and toll/interleukin-1 receptor (TIR)-domain-containing adapter-inducing interferon (TRIF) plays a significant role in infectious diseases, such as influenza A virus, Zika virus, and herpesvirus infection. An increasing number of studies have demonstrated the close association of necroptosis with multiple diseases, and disrupting necroptosis has been confirmed to be effective for treating (or managing) these diseases. The central nervous system (CNS) exhibits unique physiological structures and immune characteristics. Necroptosis may occur without the sequential activation of signal proteins, and the necroptosis of supporting cells has more important implications in disease development. Additionally, necroptotic signals can be activated in the absence of necroptosis. Here, we summarize the role of necroptosis and its signal proteins in CNS diseases and characterize typical necroptosis regulators to provide a basis for the further development of therapeutic strategies for treating such diseases. In the present review, relevant information has been consolidated from recent studies (from 2010 until the present), excluding the patents in this field.

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Section: Zika Virus and West Nile Virusmentioning

confidence: 97%

Section: Necroptosis Inhibitorsmentioning

confidence: 99%

Section: Necroptosis In Cns Diseasesmentioning

confidence: 99%

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Role of Necroptosis in Central Nervous System Diseases

Shao

Wang

et al. 2022

ACS Chem. Neurosci.

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“…In the latter scenario, necroptotic cancer cells not only attract myeloid-derived suppressor cells and/or tumor-associated macrophages and cause tumor-associated immune suppression but also release cytokines that promote angiogenesis, cancer proliferation, and metastasis (11).Necroptosis is considered to be a promising strategy in treatment evaluation of a broad spectrum of tumors (7, 12). Pagano et al reported that N6isopentenyladenosine could bypass the apoptosis resistance mechanism and induce necroptosis in GBM cells thereby offering higher therapeutic efficacy (13). However, the exact role of necroptosis in glioma has remained relatively underresearched.…”

Section: Introductionmentioning

confidence: 99%

“…Pagano et al. reported that N6-isopentenyladenosine could bypass the apoptosis resistance mechanism and induce necroptosis in GBM cells thereby offering higher therapeutic efficacy ( 13 ). However, the exact role of necroptosis in glioma has remained relatively under-researched.…”

Section: Introductionmentioning

confidence: 99%

A novel model based on necroptosis-related genes for predicting immune status and prognosis in glioma

Yuan

Jin²,

Chen³

et al. 2022

Front. Immunol.

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BackgroundGlioma is a highly aggressive brain cancer with a poor prognosis. Necroptosis is a form of programmed cell death occurring during tumor development and in immune microenvironments. The prognostic value of necroptosis in glioma is unclear. This study aimed to develop a prognostic glioma model based on necroptosis.MethodsA necroptosis-related risk model was constructed by Cox regression analysis based on The Cancer Genome Atlas (TCGA) training set, validated in two Chinese Glioma Genome Atlas (CGGA) validation sets. We explored the differences in immune infiltration and immune checkpoint genes between low and high risk groups and constructed a nomogram. Moreover, we compiled a third validation cohort including 43 glioma patients. The expression of necroptosis-related genes was verified in matched tissues using immunochemical staining in the third cohort, and we analyzed their relationship to clinicopathological features.ResultsThree necroptosis-related differentially expressed genes (EZH2, LEF1, and CASP1) were selected to construct the prognostic model. Glioma patients with a high risk score in the TCGA and CGGA cohorts had significantly shorter overall survival. The necroptosis-related risk model and nomogram exhibited good predictive performance in the TCGA training set and the CGGA validation sets. Furthermore, patients in the high risk group had higher immune infiltration status and higher expression of immune checkpoint genes, which was positively correlated with poorer outcomes. In the third validation cohort, the expression levels of the three proteins encoded by EZH2, LEF1, and CASP1 in glioma tissues were significantly higher than those from paracancerous tissues. They were also closely associated with disease severity and prognosis.ConclusionsOur necroptosis-related risk model can be used to predict the prognosis of glioma patients and improve prognostic accuracy, which may provide potential therapeutic targets and a theoretical basis for treatment.

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N6‐isopentenyladenosine inhibits aerobic glycolysis in glioblastoma cells by targeting PKM2 expression and activity

Pagano,

Coppola,

Navarra

et al. 2024

FEBS Open Bio

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Glioblastoma (GBM) is a primary tumor in the central nervous system with poor prognosis. It exhibits elevated glucose uptake and lactate production. This metabolic state of aerobic glycolysis is known as the Warburg effect. N6‐isopentenyladenosine (iPA), a natural cytokine modified with an isopentenyl moiety derived from the mevalonate pathway, has well‐established anti‐tumor activity. It inhibits cell proliferation in glioma cells, inducing cell death by apoptosis and/or necroptosis. In the present study, we found that iPA inhibits aerobic glycolysis in unmodified U87MG cells and in the same cell line engineered to over‐express wild‐type epidermal growth factor receptor (EGFR) or EGFR variant III (vIII), as well as in a primary GBM4 patient‐derived cell line. The detection of glycolysis showed that iPA treatment suppressed ATP and lactate production. We also evaluated the response of iPA treatment in normal human astrocyte primary cells, healthy counterpart cells of the brain. Aerobic glycolysis in treated normal human astrocyte cells did not show significant changes compared to GBM cells. To determine the mechanism of iPA action on aerobic glycolysis, we investigated the expression of certain enzymes involved in this metabolic pathway. We observed that iPA reduced the expression of pyruvate kinase M2 (PKM2), which plays a key role in the regulation of aerobic glycolysis, promoting tumor cell proliferation. The reduction of PKM2 expression is a result of the inhibition of the inhibitor of nuclear factor kappa‐B kinase subunit, beta/nuclear factor‐kappa B pathway upon iPA treatment. In conclusion, these experimental results show that iPA may inhibit aerobic glycolysis of GBM in stabilized cell lines and primary GBM cells by targeting the expression and activity of PKM2.

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N6-isopentenyladenosine induces cell death through necroptosis in human glioblastoma cells

Cited by 15 publications

References 29 publications

Role of Necroptosis in Central Nervous System Diseases

Role of Necroptosis in Central Nervous System Diseases

A novel model based on necroptosis-related genes for predicting immune status and prognosis in glioma

N6‐isopentenyladenosine inhibits aerobic glycolysis in glioblastoma cells by targeting PKM2 expression and activity

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