G-quadruplex ligands as potent regulators of lysosomes

Ferret, Lucille; Alvarez-Valadez, Karla; Rivière, Jennifer; Müller, Alexandra; Bohálová, Natália; Luo, Yu; Guittat, Lionel; Brázda, Václav; Kroemer, Guido; Mergny, Jean‐Louis; Djavaheri-Mergny, Mojgan

doi:10.1080/15548627.2023.2170071

Cited by 4 publications

(3 citation statements)

References 106 publications

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“…G4 ligand induced autophagy can be a function of several pathways including cellular stress responses or lysosomal drug sequestration resulting in lysosomal membrane permeabilization 51 . For example, treatment of cervical cancer and osteosarcoma cells with G4 ligand 20A resulted in an enrichment of RNA and proteins involved in the lysosomal pathway accompanied by MTOR inhibition, global DNA damage and activation of autophagy that causes onset of senescence and protects the cell from cell death 16 , 52 .…”

Section: Discussionmentioning

confidence: 99%

G-quadruplexes in MTOR and induction of autophagy

Majumder,

Shukla,

Arya

et al. 2024

Sci Rep

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G-quadruplex (G4) structures have emerged as singular therapeutic targets for cancer and neurodegeneration. Autophagy, a crucial homeostatic mechanism of the cell, is often dysregulated in neurodegenerative diseases and cancers. We used QGRS mapper to identify 470 G4 sequences in MTOR, a key negative regulator of autophagy. We sought to identify a functional context by leveraging the effect of G4-targeting ligands on MTOR G4 sequences. The effect of Bis-4,3, a G4 selective dimeric carbocyanine dye, was compared with the known G4-stabilizing activity of the porphyrin, TMPyP4 in HeLa and SHSY-5Y cells. Our results show that treatment with G4-selective ligands downregulates MTOR RNA and mTOR protein expression levels. This is the first report describing G4 motifs in MTOR. This study indicates a possible role of G4 stabilizing ligands in induction of autophagy by downregulation of mTOR levels, albeit not precluding MTOR independent pathways.

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Section: Discussionmentioning

confidence: 99%

G-quadruplexes in MTOR and induction of autophagy

Majumder,

Shukla,

Arya

et al. 2024

Sci Rep

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“…Whether autophagy plays a role in promoting or suppressing cancer is still debated.It can either promote or inhibit the growth of malignant tumors. This suggests that autophagy may play different roles in different stages of tumorigenesis [13][14][15]. Nevertheless, the function and process of autophagy in the immune response to ovarian cancer remain uncertain.…”

Section: Introductionmentioning

confidence: 99%

XPR1 promotes ovarian cancer growth and regulates MHC-I through autophagy

hu,

Wang,

Luo

et al. 2024

Preprint

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Introduction: Immune checkpoint inhibitors have a poor effect in treating ovarian cancer, and the specific mechanism is unknown. The purpose of this research was to investigate the impact of XPR1 on controlling autophagy in ovarian cancer. Methods: We use CRISPR/Cas9 knockout library to screen the potential genes of autophagy regulating in ovarian cancer. Inhibiting and increasing XPR1 levels revealed the impact of XPR1 on ovarian cancer growth through both in vivo and in vitro experiments; the connection between XPR1 and LAMP1 was identified using co-immunoprecipitation; and the influence of XPR1 on subsequent protein expression was assessed through western blot analysis. Results: The findings suggested an increase in XPR1 expression in ovarian cancer tissues. The elevated level of its expression was linked to the stage of ovarian cancer, as well as overall survival (OS) and progression-free survival (PFS). XPR1 enhanced the growth and spread of ovarian cancer while suppressing autophagy. Moreover, XPR1 suppressed autophagy flux by interacting with LAMP1 and the PI3K/Akt/mTOR pathway. XPR1 controlled the positioning and production of MHC-I molecules on the surfaces of ovarian cancer cells via autophagy. Silencing XPR1 combined with autophagy inhibitor chloroquine significantly inhibited tumor growth in mouse ovarian cancer models. In conclusion, the findings indicate that XPR1 could serve as a promising target for the diagnosis and treatment of ovarian cancer. Combined autophagy inhibitors may improve the sensitivity of ovarian cancer immunotherapy.

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“…Epigenetic abnormalities are observed at the onset and during the progression of age-related diseases, such as AD ( Cavalli and Heard, 2019 ). The global DNA methylation pattern decreases with aging and contributes to aging-associated heterochromatin loss, and some genomic regions are also characterized by age-related locus-specific hypermethylation ( Xiao et al, 2019 ; Ferret et al, 2023 ). Nevertheless, much progress has been made in understanding the genetic basis of AD in which multiple loci have been discovered.…”

Section: Introductionmentioning

confidence: 99%

G-quadruplexes and associated proteins in aging and Alzheimer’s disease

Kumar¹,

Morales

Tsvetkov

2023

Front. Aging

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Aging is a prominent risk factor for many neurodegenerative disorders, such as Alzheimer’s disease (AD). Alzheimer’s disease is characterized by progressive cognitive decline, memory loss, and neuropsychiatric and behavioral symptoms, accounting for most of the reported dementia cases. This disease is now becoming a major challenge and burden on modern society, especially with the aging population. Over the last few decades, a significant understanding of the pathophysiology of AD has been gained by studying amyloid deposition, hyperphosphorylated tau, synaptic dysfunction, oxidative stress, calcium dysregulation, and neuroinflammation. This review focuses on the role of non-canonical secondary structures of DNA/RNA G-quadruplexes (G4s, G4-DNA, and G4-RNA), G4-binding proteins (G4BPs), and helicases, and their roles in aging and AD. Being critically important for cellular function, G4s are involved in the regulation of DNA and RNA processes, such as replication, transcription, translation, RNA localization, and degradation. Recent studies have also highlighted G4-DNA’s roles in inducing DNA double-strand breaks that cause genomic instability and G4-RNA’s participation in regulating stress granule formation. This review emphasizes the significance of G4s in aging processes and how their homeostatic imbalance may contribute to the pathophysiology of AD.

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G-quadruplex ligands as potent regulators of lysosomes

Cited by 4 publications

References 106 publications

G-quadruplexes in MTOR and induction of autophagy

G-quadruplexes in MTOR and induction of autophagy

XPR1 promotes ovarian cancer growth and regulates MHC-I through autophagy

G-quadruplexes and associated proteins in aging and Alzheimer’s disease

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