Inhibition of Intermedin (Adrenomedullin 2) Suppresses the Growth of Glioblastoma and Increases the Antitumor Activity of Temozolomide

Huang, Lüping; Wang, Denian; Feng, Zongyun; Zhao, Huan; Xiao, Fei; Yue, Wei; Zhang, Heng; Li, Hongyu; Kong, Lingmiao; Li, Min; Liu, Fei; Zhang, Haili; Zhang, Wei

doi:10.1158/1535-7163.mct-20-0619

Cited by 7 publications

(8 citation statements)

References 32 publications

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“…ADM has been reported as one of 5 candidate genes associated with glioma resistance to TMZ, which showed to be consistently linked to higher expression of DDIT4 and lower prognosis in TMZ-treated cells [ 46 ]. Adrenomedullin 2, another CGRP member, increased glioma cell invasion and proliferation via enhancing the formation of filopodia, which depends on the activation of Erk1/2 pathway [ 47 ]. In this study, ADM expression has been found upregulated in TMZ -resistant glioma samples, suggesting the underlying effect of ADM on glioma cell TMZ resistance.…”

Section: Discussionmentioning

confidence: 99%

miR-1297 sensitizes glioma cells to temozolomide (TMZ) treatment through targeting adrenomedullin (ADM)

Cheng

et al. 2022

J Transl Med

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Background Gliomas account for about 80% of all malignant brain and other central nervous system (CNS) tumors. Temozolomide (TMZ) resistance represents a major treatment hurdle. Adrenomedullin (ADM) has been reported to induce glioblastoma cell growth. Methods Cell viability was measured using the CCK-8 assay. The apoptosis analysis was performed using the Annexin V-FITC Apoptosis Detection Kit. The mitochondrial membrane potential was determined by JC-1 staining. A nude mouse tumor assay was used to detect tumor formation. Hematoxylin and eosin (H&E) and immunohistochemical (IHC) staining were performed in tissue sections. Activation of Akt and Erk and expression of apoptosis-related proteins were determined by immunoblotting. Results ADM expression has been found upregulated in TMZ -resistant glioma samples based on bioinformatics and experimental analyses. Knocking down ADM in glioma cells enhanced the suppressive effects of TMZ on glioma cell viability, promotive effects on cell apoptosis, and inhibitory effects on mitochondrial membrane potential. Moreover, ADM knockdown also enhanced TMZ effects on Bax/Bcl-2, Akt phosphorylation, and Erk1/2 phosphorylation. Bioinformatics and experimental investigation indicated that miR-1297 directly targeted ADM and inhibited ADM expression. miR-1297 overexpression exerted similar effects to ADM knockdown on TMZ-treated glioma cells. More importantly, under TMZ treatment, inhibition of miR-1297 attenuated TMZ treatment on glioma cells; ADM knockdown partially attenuated the effects of miR-1297 inhibition on TMZ-treated glioma cells. Conclusions miR-1297 sensitizes glioma cells to TMZ treatment through targeting ADM. The Bax/Bcl-2, Akt, and Erk1/2 signaling pathways, as well as mitochondrial functions might be involved.

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Section: Discussionmentioning

confidence: 99%

miR-1297 sensitizes glioma cells to temozolomide (TMZ) treatment through targeting adrenomedullin (ADM)

Cheng

et al. 2022

J Transl Med

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“…As expected, GBM had the highest expression of ADM2 . The ADM2 promoted GBM cell proliferation by activating ERK1/2 phosphorylation [ 57 ]. BMP2 and BMP8 are ligands of the transforming growth factor- β (TGF- β ) family [ 58 ].…”

Section: Discussionmentioning

confidence: 99%

An Immune-Related Prognostic Signature for Predicting Clinical Outcomes and Immune Landscape in IDH-Mutant Lower-Grade Gliomas

Xiao

Gao

et al. 2021

Journal of Oncology

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Background. IDH mutation is the most common in diffuse LGGs, correlated with a favorable prognosis. However, the IDH-mutant LGGs patients with poor prognoses need to be identified, and the potential mechanism leading to a worse outcome and treatment options needs to be investigated. Methods. A six-gene immune-related prognostic signature in IDH-mutant LGGs was constructed based on two public datasets and univariate, multivariate, and LASSO Cox regression analysis. Patients were divided into low- and high-risk groups based on the median risk score in the training and validation sets. We analyzed enriched pathways and immune cell infiltration, applying the GSEA and the immune evaluation algorithms. Results. Stratification and multivariate Cox analysis unveiled that the six-gene signature was an independent prognostic factor. The signature (0.806/0.795/0.822) showed a remarkable prognostic performance, with 1-, 3-, and 5-year time-dependent AUC, higher than for grade (0.612/0.638/0.649) and 1p19q codeletion status (0.606/0.658/0.676). High-risk patients had higher infiltrating immune cells. However, the specific immune escape was observed in the high-risk group after immune activation, owing to increasing immunosuppressive cells, inhibitory cytokines, and immune checkpoint molecules. Moreover, a novel nomogram model was developed to evaluate the survival in IDH-mutant LGGs patients. Conclusion. The six-gene signature could be a promising prognostic biomarker, which is promising to promote individual therapy and improve the clinical outcomes of IDH-mutant gliomas. The study also refined the current classification system of IDH-mutant gliomas, classifying patients into two subtypes with distinct immunophenotypes and overall survival.

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“…AM2 expression increased and correlated with higher-grade gliomas [ 222 ]. AM2 promotes filopodia formation, increasing the invasive capacity of glioma cells, and the activation of ERK1/2 has been involved in the proliferation, invasion, and malignancy of glioblastoma cells [ 222 ].…”

Section: Involvement Of the Tachykinin And Calcitonin/calcitonin Gene...mentioning

confidence: 99%

Peptidergic Systems and Cancer: Focus on Tachykinin and Calcitonin/Calcitonin Gene-Related Peptide Families

Sánchez

Rodríguez

Coveñas

2023

Cancers

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The roles played by the peptides belonging to the tachykinin (neurokinin A and B) and calcitonin/calcitonin gene-related peptide (adrenomedullin, adrenomedullin 2, amylin, and calcitonin gene-related peptide (CGRP)) peptide families in cancer development are reviewed. The structure and dynamics of the neurokinin (NK)-2, NK-3, and CGRP receptors are studied together with the intracellular signaling pathways in which they are involved. These peptides play an important role in many cancers, such as breast cancer, colorectal cancer, glioma, lung cancer, neuroblastoma, oral squamous cell carcinoma, phaeochromocytoma, leukemia, bladder cancer, endometrial cancer, Ewing sarcoma, gastric cancer, liver cancer, melanoma, osteosarcoma, ovarian cancer, pancreatic cancer, prostate cancer, renal carcinoma, and thyroid cancer. These peptides are involved in tumor cell proliferation, migration, metastasis, angiogenesis, and lymphangiogenesis. Several antitumor therapeutic strategies, including peptide receptor antagonists, are discussed. The main research lines to be developed in the future are mentioned.

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Inhibition of Intermedin (Adrenomedullin 2) Suppresses the Growth of Glioblastoma and Increases the Antitumor Activity of Temozolomide

Cited by 7 publications

References 32 publications

miR-1297 sensitizes glioma cells to temozolomide (TMZ) treatment through targeting adrenomedullin (ADM)

miR-1297 sensitizes glioma cells to temozolomide (TMZ) treatment through targeting adrenomedullin (ADM)

An Immune-Related Prognostic Signature for Predicting Clinical Outcomes and Immune Landscape in IDH-Mutant Lower-Grade Gliomas

Peptidergic Systems and Cancer: Focus on Tachykinin and Calcitonin/Calcitonin Gene-Related Peptide Families

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