RRM2 Mediates the Anti-Tumor Effect of the Natural Product Pectolinarigenin on Glioblastoma Through Promoting CDK1 Protein Degradation by Increasing Autophagic Flux

Jiang, Haiping; Zhang, Dongzhi; Aleksandrovich, Karpov Denis; Ye, Junyi; Wang, Lixiang; Chen, Xiaofeng; Gao, Ming; Wang, Xinzhuang; Yan, Tao; He, Yang; Lu, Enzhou; Liu, Wenwu; Zhang, Cheng; Wu, Jianing; Yao, Penglei; Sun, Zhenying; Rong, Xuan; Timofeevich, Sokhatskii Andrei; Mahmutovich, Safin Shamil; Zheng, Zhixing; Chen, Xin; Zhao, Shiguang

doi:10.3389/fonc.2022.887294

Cited by 5 publications

(5 citation statements)

References 43 publications

(48 reference statements)

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“…This is in good agreement with the data on the severe delay in colony formation and reduced survival of wild-type yeast under the conditions of 4-NQO action [21,22]. Similarly, in mammals, various modes of transcriptional repression or targeting RRM2 result in the suppression of tumor growth, including GBM [44,59,60]. RNR catalyzes the synthesis of dNTP by a radical mechanism [24], which can be counteracted by the formation of reactive oxygen species.…”

Section: Discussionsupporting

confidence: 89%

Synergistic Effect of a Combination of Proteasome and Ribonucleotide Reductase Inhibitors in a Biochemical Model of the Yeast Saccharomyces cerevisiae and a Glioblastoma Cell Line

Kulagin,

Starodubova,

Osipova

et al. 2024

IJMS

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Proteasome inhibitors are used in the therapy of several cancers, and clinical trials are underway for their use in the treatment of glioblastoma (GBM). However, GBM becomes resistant to chemotherapy relatively rapidly. Recently, the overexpression of ribonucleotide reductase (RNR) genes was found to mediate therapy resistance in GBM. The use of combinations of chemotherapeutic agents is considered a promising direction in cancer therapy. The present work aimed to evaluate the efficacy of the combination of proteasome and RNR inhibitors in yeast and GBM cell models. We have shown that impaired proteasome function results in increased levels of RNR subunits and increased enzyme activity in yeast. Co-administration of the proteasome inhibitor bortezomib and the RNR inhibitor hydroxyurea was found to significantly reduce the growth rate of S. cerevisiae yeast. Accordingly, the combination of bortezomib and another RNR inhibitor gemcitabine reduced the survival of DBTRG-05MG compared to the HEK293 cell line. Thus, yeast can be used as a simple model to evaluate the efficacy of combinations of proteasome and RNR inhibitors.

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Section: Discussionsupporting

confidence: 89%

Synergistic Effect of a Combination of Proteasome and Ribonucleotide Reductase Inhibitors in a Biochemical Model of the Yeast Saccharomyces cerevisiae and a Glioblastoma Cell Line

Kulagin,

Starodubova,

Osipova

et al. 2024

IJMS

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“…Our prognostic model showed low levels of MPC1 expression and high levels of STAT3, RRM2, and TLR4 expression, suggesting a poor prognosis for GBM patients, which was in agreement with previous studies 37–42 . However, our study differed from previous studies in several aspects.…”

Section: Discussionsupporting

confidence: 89%

Warburg effect‐related risk scoring model to assess clinical significance and immunity characteristics of glioblastoma

Zhang,

Wang,

Zheng

et al. 2023

Cancer Medicine

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BackgroundGlioblastoma (GBM), the most common primary malignant brain tumor, has a poor prognosis, with a median survival of only 14.6 months. The Warburg effect is an abnormal energy metabolism, which is the main cause of the acidic tumor microenvironment. This study explored the role of the Warburg effect in the prognosis and immune microenvironment of GBM.MethodsA prognostic risk score model of Warburg effect‐related genes (Warburg effect signature) was constructed using GBM cohort data from The Cancer Genome Atlas. Cox analysis was performed to identify independent prognostic factors. Next, the nomogram was built to predict the prognosis for GBM patients. Finally, the drug sensitivity analysis was utilized to find the drugs that specifically target Warburg effect‐related genes.ResultsAge, radiotherapy, chemotherapy, and WRGs score were confirmed as independent prognostic factors for GBM by Cox analyses. The C‐index (0.633 for the training set and 0.696 for the validation set) and area under curve (>0.7) indicated that the nomogram exhibited excellent performance. The calibration curve also indicates excellent consistency of the nomogram between predictions and actual observations. In addition, immune microenvironment analysis revealed that patients with high WRGs scores had high immunosuppressive scores, a high abundance of immunosuppressive cells, and a low response to immunotherapy. The Cell Counting Kit‐8 assays showed that the drugs targeting Warburg effect‐related genes could inhibit the GBM cells growth in vitro.ConclusionOur research showed that the Warburg effect is connected with the prognosis and immune microenvironment of GBM. Therefore, targeting Warburg effect‐related genes may provide novel therapeutic options.

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“… 42 Jiang found that pectolinarigenin promoted autophagic flux through RRM2 suppression, consequently inhibiting the invasion of glioma cells. 43 However, whether tumor antigens can elicit an immune response also depends on the TIME. Due to the high heterogeneity of glioma, only a subset of LGG patients may benefit from mRNA vaccines.…”

Section: Discussionmentioning

confidence: 99%

Identification of Lower Grade Glioma Antigens Based on Ferroptosis Status for mRNA Vaccine Development

Zhao,

Xing,

Guo

et al. 2024

PGPM

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mRNA vaccines represent a promising and innovative strategy within the realm of cancer immunotherapy. However, their efficacy in treating lower-grade glioma (LGG) requires evaluation. Ferroptosis exhibits close associations with the initiation, evolution, and suppression of cancer. In this study, we explored the landscape of the ferroptosis-associated tumor microenvironment to facilitate the development of mRNA vaccines for LGG patients. Patients and Methods: Genomic and clinical data of the LGG patients was obtained from the Cancer Genome Atlas (TCGA) and Chinese Glioma Genome Atlas (CGGA) databases. Ferroptosis-related tumor antigens were identified based on differential expression, mutation status, correlation with antigen-presenting cells, and prognosis, relevance to immunogenic cell death (ICD). Antigen expression levels in LGG specimens and cell lines were validated using real time-polymerase chain reaction (RT-PCR). Consensus clustering was employed for patient classification. The immune landscapes of ferroptosis subtypes were further characterized, including immune responses, prognostic ability, tumor microenvironment, and tumor-related signatures. Results: Five tumor antigens, namely, HOTAIR, IDO1, KIF20A, NR5A2, and RRM2 were identified in LGG. RT-PCR demonstrated higher expression of these genes in LGG compared to the control. Twelve gene modules and four ferroptosis subtypes (FS1-FS4) of LGG were defined. FS2 and FS4, characterized as "cold" tumors due to their decreased tumor mutation burden (TMB) and immune checkpoint proteins (ICPs), were deemed appropriate candidates for the mRNA vaccine. Conclusion: HOTAIR, IDO1, KIF20A, NR5A2, and RRM2 were identified as promising candidate antigens for the development of an LGG mRNA vaccine, particularly offering potential benefits to FS2 and FS4 patients.

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RRM2 Mediates the Anti-Tumor Effect of the Natural Product Pectolinarigenin on Glioblastoma Through Promoting CDK1 Protein Degradation by Increasing Autophagic Flux

Cited by 5 publications

References 43 publications

Synergistic Effect of a Combination of Proteasome and Ribonucleotide Reductase Inhibitors in a Biochemical Model of the Yeast Saccharomyces cerevisiae and a Glioblastoma Cell Line

Synergistic Effect of a Combination of Proteasome and Ribonucleotide Reductase Inhibitors in a Biochemical Model of the Yeast Saccharomyces cerevisiae and a Glioblastoma Cell Line

Warburg effect‐related risk scoring model to assess clinical significance and immunity characteristics of glioblastoma

Identification of Lower Grade Glioma Antigens Based on Ferroptosis Status for mRNA Vaccine Development

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