FIN56, a novel ferroptosis inducer, triggers lysosomal membrane permeabilization in a TFEB-dependent manner in glioblastoma

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Abstract

Objective: To explore the anti-tumor effect of FIN56, a novel ferroptosis inducer, on glioblastoma and its underlying mechanisms.

Methods: Two human glioblastoma cell lines, LN229 and U118 were applied in this study. Anti-tumor effect was measured by CCK-8 assay, EdU assay and cell cycle analysis. Fluorescent probes, immunofluorescence, plasmid transfection, shRNA knocking out, reverse transcription PCR, western blot analysis, and transmission electron microscopy were used to study the underlying mechanisms. At last, a subcutaneous nude mice model was used to study the anti-tumor effect of FIN56 in vivo. The GraphPad Prism software program was applied for statistical analysis.

Results: FIN56 decreased cell viability, inhibited cell proliferation and caused cell cycle arrest on LN229 and U118 cells. Further study showed that FIN56 induced ferroptosis and induced lysosomal membrane permeabilization in a ferroptosis and transfactor EB dependent manner. Animal study demonstrated that FIN56 inhibited glioma growth and caused ferroptosis in vivo.

Conclusion: FIN56 is a promising anti-tumor compound.

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Most cited references 28

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Ferroptosis: an iron-dependent form of nonapoptotic cell death.

Scott J. Dixon, Kathryn Lemberg, Michael Lamprecht … (2012)

Nonapoptotic forms of cell death may facilitate the selective elimination of some tumor cells or be activated in specific pathological states. The oncogenic RAS-selective lethal small molecule erastin triggers a unique iron-dependent form of nonapoptotic cell death that we term ferroptosis. Ferroptosis is dependent upon intracellular iron, but not other metals, and is morphologically, biochemically, and genetically distinct from apoptosis, necrosis, and autophagy. We identify the small molecule ferrostatin-1 as a potent inhibitor of ferroptosis in cancer cells and glutamate-induced cell death in organotypic rat brain slices, suggesting similarities between these two processes. Indeed, erastin, like glutamate, inhibits cystine uptake by the cystine/glutamate antiporter (system x(c)(-)), creating a void in the antioxidant defenses of the cell and ultimately leading to iron-dependent, oxidative death. Thus, activation of ferroptosis results in the nonapoptotic destruction of certain cancer cells, whereas inhibition of this process may protect organisms from neurodegeneration. Copyright © 2012 Elsevier Inc. All rights reserved.

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Ferroptosis: molecular mechanisms and health implications

Daolin Tang, Xin CHEN, Rui Kang … (2020)

Cell death can be executed through different subroutines. Since the description of ferroptosis as an iron-dependent form of non-apoptotic cell death in 2012, there has been mounting interest in the process and function of ferroptosis. Ferroptosis can occur through two major pathways, the extrinsic or transporter-dependent pathway and the intrinsic or enzyme-regulated pathway. Ferroptosis is caused by a redox imbalance between the production of oxidants and antioxidants, which is driven by the abnormal expression and activity of multiple redox-active enzymes that produce or detoxify free radicals and lipid oxidation products. Accordingly, ferroptosis is precisely regulated at multiple levels, including epigenetic, transcriptional, posttranscriptional and posttranslational layers. The transcription factor NFE2L2 plays a central role in upregulating anti-ferroptotic defense, whereas selective autophagy may promote ferroptotic death. Here, we review current knowledge on the integrated molecular machinery of ferroptosis and describe how dysregulated ferroptosis is involved in cancer, neurodegeneration, tissue injury, inflammation, and infection.

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TFEB links autophagy to lysosomal biogenesis.

Carmine Settembre, Chiara Di Malta, Vinicia Polito … (2011)

Autophagy is a cellular catabolic process that relies on the cooperation of autophagosomes and lysosomes. During starvation, the cell expands both compartments to enhance degradation processes. We found that starvation activates a transcriptional program that controls major steps of the autophagic pathway, including autophagosome formation, autophagosome-lysosome fusion, and substrate degradation. The transcription factor EB (TFEB), a master gene for lysosomal biogenesis, coordinated this program by driving expression of autophagy and lysosomal genes. Nuclear localization and activity of TFEB were regulated by serine phosphorylation mediated by the extracellular signal-regulated kinase 2, whose activity was tuned by the levels of extracellular nutrients. Thus, a mitogen-activated protein kinase-dependent mechanism regulates autophagy by controlling the biogenesis and partnership of two distinct cellular organelles.

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Author and article information

Journal

Journal ID (nlm-ta): J Cancer

Journal ID (iso-abbrev): J Cancer

Journal ID (publisher-id): jca

Title: Journal of Cancer

Publisher: Ivyspring International Publisher (Sydney )

ISSN (Electronic): 1837-9664

Publication date Collection: 2021

Publication date (Electronic): 13 September 2021

Volume: 12

Issue: 22

Pages: 6610-6619

Affiliations

[1 ]Department of Neurosurgery, Qilu Hospital of Shandong University and Institute of Brain and Brain-Inspired Science, Shandong University, Jinan, China.

[2 ]Shandong Key Laboratory of Brain Function Remodeling, Jinan, China.

[3 ]Department of Neurosurgery, Heze third people's hospital, Heze, China.

Author notes

✉ Corresponding author: Lizhang Han, Department of Neurosurgery, Qilu Hospital of Shandong University and Institute of Brain and Brain-Inspired Science, Shandong University, Jinan, China. E-mail: QL-hanlizhang@ 123456sdu.edu.cn .

Competing Interests: The authors have declared that no competing interest exists.

Article

Publisher ID: jcav12p6610

DOI: 10.7150/jca.58500

PMC ID: 8517990

PubMed ID: 34659551

SO-VID: fe2b0ded-afbb-4995-8ec8-dae41e15299a

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This is an open access article distributed under the terms of the Creative Commons Attribution License ( https://creativecommons.org/licenses/by/4.0/). See http://ivyspring.com/terms for full terms and conditions.

FIN56, a novel ferroptosis inducer, triggers lysosomal membrane permeabilization in a TFEB-dependent manner in glioblastoma

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Karger: Oncology

Most cited references 28

Ferroptosis: an iron-dependent form of nonapoptotic cell death.

Ferroptosis: molecular mechanisms and health implications

TFEB links autophagy to lysosomal biogenesis.

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