ConBr lectin modulates MAPKs and Akt pathways and triggers autophagic glioma cell death by a mechanism dependent upon caspase-8 activation

Wolin, Ingrid A.V.; Heinrich, Isabella A.; Nascimento, Ana Paula Machado; Welter, Priscilla Gomes; Sosa, Liliana del Valle; Paul, Ana Lucía De; Zanotto-Filho, Alfeu; Nedel, Cláudia Beatriz; Lima, Lara Dias; Osterne, Vinicius Jose Da Silva; Pinto-Junior, Vanir Reis; Nascimento, Kyria S.; Cavada, Benildo Sousa; Leal, Rodrigo Bainy

doi:10.1016/j.biochi.2020.11.003

Cited by 17 publications

(15 citation statements)

References 104 publications

(137 reference statements)

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“…Gliomas are a heterogeneous group of central nervous system tumors that still lack efficient treatment methods regardless of medical progress [ 1 ]. Despite multimodal treatment, consisting of surgical procedures, radiotherapy, and chemotherapy, the median survival for glioblastoma patients is only 12–14 months [ 2 , 3 ]. Recent studies of the molecular profile of gliomas show the complex dynamics of tumor progression and explain the evolution of mutations of this biologically aggressive group of tumors [ 4 ].…”

Section: Introductionmentioning

confidence: 99%

Integrative cBioPortal Analysis Revealed Molecular Mechanisms That Regulate EGFR-PI3K-AKT-mTOR Pathway in Diffuse Gliomas of the Brain

Brlek

Kafka

Bukovac

et al. 2021

Cancers

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Diffuse gliomas are a heterogeneous group of tumors with aggressive biological behavior and a lack of effective treatment methods. Despite new molecular findings, the differences between pathohistological types still require better understanding. In this in silico analysis, we investigated AKT1, AKT2, AKT3, CHUK, GSK3β, EGFR, PTEN, and PIK3AP1 as participants of EGFR-PI3K-AKT-mTOR signaling using data from the publicly available cBioPortal platform. Integrative large-scale analyses investigated changes in copy number aberrations (CNA), methylation, mRNA transcription and protein expression within 751 samples of diffuse astrocytomas, anaplastic astrocytomas and glioblastomas. The study showed a significant percentage of CNA in PTEN (76%), PIK3AP1 and CHUK (75% each), EGFR (74%), AKT2 (39%), AKT1 (32%), AKT3 (19%) and GSK3β (18%) in the total sample. Comprehensive statistical analyses show how genomics and epigenomics affect the expression of examined genes differently across various pathohistological types and grades, suggesting that genes AKT3, CHUK and PTEN behave like tumor suppressors, while AKT1, AKT2, EGFR, and PIK3AP1 show oncogenic behavior and are involved in enhanced activity of the EGFR-PI3K-AKT-mTOR signaling pathway. Our findings contribute to the knowledge of the molecular differences between pathohistological types and ultimately offer the possibility of new treatment targets and personalized therapies in patients with diffuse gliomas.

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Section: Introductionmentioning

confidence: 99%

Integrative cBioPortal Analysis Revealed Molecular Mechanisms That Regulate EGFR-PI3K-AKT-mTOR Pathway in Diffuse Gliomas of the Brain

Brlek

Kafka

Bukovac

et al. 2021

Cancers

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“…Previously, ConA was found to induce antitumor activity through autophagy in different types of cancer, such as hepatoma [ 19 ], cervical cancer [ 20 ], and glioblastoma [ 9 , 10 , 11 ]. Among different proposed mechanisms is the interaction between the lectin and glycans associated with proteins present on the plasma membrane, triggering intracellular signaling processes [ 12 , 21 ]. Hence, intracellular targets can be modulated through these processes, including mitochondria, with the generation of the reactive oxygen species (ROS) and cytochrome C release, followed by the modulation of caspases and autophagy [ 12 , 21 ].…”

Section: Resultsmentioning

confidence: 99%

“…Among different proposed mechanisms is the interaction between the lectin and glycans associated with proteins present on the plasma membrane, triggering intracellular signaling processes [ 12 , 21 ]. Hence, intracellular targets can be modulated through these processes, including mitochondria, with the generation of the reactive oxygen species (ROS) and cytochrome C release, followed by the modulation of caspases and autophagy [ 12 , 21 ]. Moreover, through the modulation of Ras/ERK1/2, PI3K/Akt, mTORC1, and NF-kB, plant lectins may trigger these cell fates, especially autophagic cell death [ 10 , 11 , 12 , 21 ].…”

Section: Resultsmentioning

confidence: 99%

“…Some of these lectins were able to alter the mitochondrial membrane potential, cell migration, and induce morphological changes in cells. A colorimetric and biochemical analysis indicated cell death by autophagy, apoptosis, and/or necrosis via mitochondrial modulation and metalloproteinases [ 9 , 10 , 11 , 12 ]. Despite all these observations, specific molecular targets for legume lectins that trigger tumor cytotoxicity have not been identified.…”

Section: Introductionmentioning

confidence: 99%

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Structural Prediction and Characterization of Canavalia grandiflora (ConGF) Lectin Complexed with MMP1: Unveiling the Antiglioma Potential of Legume Lectins

et al. 2022

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A glioblastoma (GBM) is a highly malignant primary brain tumor with a poor prognosis because of its invasiveness and high resistance to current therapies. In GBMs, abnormal glycosylation patterns are associated with malignancy, which allows for the use of lectins as tools for recognition and therapy. More specifically, lectins can interact with glycan structures found on the malignant cell surface. In this context, the present work aimed to investigate the antiglioma potential of ConGF, a lectin purified from Canavalia grandiflora seeds, against C6 cells. The treatment of C6 cells with ConGF impaired the mitochondrial transmembrane potential, reduced cell viability, and induced morphological changes. ConGF also induced massive autophagy, as evaluated by acridine orange (AO) staining and LC3AB-II expression, but without prominent propidium iodide (PI) labeling. The mechanism of action appears to involve the carbohydrate-binding capacity of ConGF, and in silico studies suggested that the lectin can interact with the glycan structures of matrix metalloproteinase 1 (MMP1), a prominent protein found in malignant cells, likely explaining the observed effects.

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“…SAnDReS aims to integrate all necessary steps to create machine learning models in one suite of programs [44]. SAnDReS has been applied to a wide range of different protein systems [125][126][127][128][129][130][131][132][133][134][135][136][137][138][139][140][141][142][143] and has successfully generated machine learning models that outperform classical scoring functions in the prediction of binding affinity [45,[144][145][146][147][148][149][150][151].…”

Section: Binding Affinity With Sandresmentioning

confidence: 99%

Computational Prediction of Binding Affinity for CDK2-ligand Complexes. A Protein Target for Cancer Drug Discovery

Veit-Acosta

Azevedo

2022

CMC

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Background: CDK2 participates in the control of eukaryotic cell-cycle progression. Due to the great interest in CDK2 for drug development and the relative easiness in crystallizing this enzyme, we have over 400 structural studies focused on this protein target. This structural data is the basis for the development of computational models to estimate CDK2-ligand binding affinity. Objective: This work focuses on the recent developments in the application of supervised machine learning modeling to develop scoring functions to predict the binding affinity of CDK2. Method: We employed the structures available at the protein data bank and the ligand information accessed from the BindingDB, Binding MOAD, and PDBbind to evaluate the predictive performance of machine learning techniques combined with physical modeling used to calculate binding affinity. We compared this hybrid methodology with classical scoring functions available in docking programs. Results: Our comparative analysis of previously published models indicated that a model created using a combination of a mass-spring system and cross-validated Elastic Net to predict the binding affinity of CDK2-inhibitor complexes outperformed classical scoring functions available in AutoDock4 and AutoDock Vina. Conclusion: All studies reviewed here suggest that targeted machine learning models are superior to classical scoring functions to calculate binding affinities. Specifically for CDK2, we see that the combination of physical modeling with supervised machine learning techniques exhibits improved predictive performance to calculate the protein-ligand binding affinity. These results find theoretical support in the application of the concept of scoring function space.

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ConBr lectin modulates MAPKs and Akt pathways and triggers autophagic glioma cell death by a mechanism dependent upon caspase-8 activation

Cited by 17 publications

References 104 publications

Integrative cBioPortal Analysis Revealed Molecular Mechanisms That Regulate EGFR-PI3K-AKT-mTOR Pathway in Diffuse Gliomas of the Brain

Integrative cBioPortal Analysis Revealed Molecular Mechanisms That Regulate EGFR-PI3K-AKT-mTOR Pathway in Diffuse Gliomas of the Brain

Structural Prediction and Characterization of Canavalia grandiflora (ConGF) Lectin Complexed with MMP1: Unveiling the Antiglioma Potential of Legume Lectins

Computational Prediction of Binding Affinity for CDK2-ligand Complexes. A Protein Target for Cancer Drug Discovery

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