Inhibition of autophagy increases susceptibility of glioblastoma stem cells to temozolomide by igniting ferroptosis

Buccarelli, Mariachiara; Marconi, Matteo; Pacioni, Simone; Pascalis, Ivana De; D’Alessandris, Quintino Giorgio; Martini, Maurizio; Ascione, Barbara; Malorni, Walter; Larocca, Luigi Maria; Pallini, Roberto; Ricci–Vitiani, Lucia; Matarrese, Paola

doi:10.1038/s41419-018-0864-7

Cited by 201 publications

(157 citation statements)

References 65 publications

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“…TMZ selectively induced GSCs to undergo ferroptosis but not apoptosis or necrosis in TMZ‐induced cell death during treatment. That result also showed the sensitivity of ferroptosis induction in brain tumours …”

Section: Main Textmentioning

confidence: 55%

Molecular mechanisms of ferroptosis and its role in cancer therapy

Ding

et al. 2019

J Cellular Molecular Medi

480

347

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Ferroptosis is a newly defined programmed cell death process with the hallmark of the accumulation of iron‐dependent lipid peroxides. The term was first coined in 2012 by the Stockwell Lab, who described a unique type of cell death induced by the small molecules erastin or RSL3. Ferroptosis is distinct from other already established programmed cell death and has unique morphological and bioenergetic features. The physiological role of ferroptosis during development has not been well characterized. However, ferroptosis shows great potentials during the cancer therapy. Great progress has been made in exploring the mechanisms of ferroptosis. In this review, we focus on the molecular mechanisms of ferroptosis, the small molecules functioning in ferroptosis initiation and ferroptosis sensitivity in different cancers. We are also concerned with the new arising questions in this particular research area that remains unanswered.

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Section: Main Textmentioning

confidence: 55%

Molecular mechanisms of ferroptosis and its role in cancer therapy

Ding

et al. 2019

J Cellular Molecular Medi

480

347

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“…32,33 Autophagy may function either as a cell survival mechanism under specific conditions, or as a second type of programmed cell death. 34,35 Several reports have highlighted the participation of autophagy regulation in different cancers, including OS. 36,37 In the present study, we showed that miR-193b significantly increases the expression of autophagy-related proteins in OS cells and promotes cell sensitivity to epirubicin treatment, indicating that miR-193b-induced OS cell apoptosis may be autophagy-dependent.…”

Section: Discussionmentioning

confidence: 99%

<p>miR-193b Increases the Chemosensitivity of Osteosarcoma Cells by Promoting FEN1-Mediated Autophagy</p>

Dong¹,

Ye²,

Ma³

et al. 2019

OTT

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Background: Osteosarcoma (OS) is one of the most common malignant bone tumors and specific microRNAs (miRNAs) are closely associated with malignant OS progression. In this study, we examined the role of and the involvement of autophagy and apoptosis in the chemosensitivity of OS cells. Methods: We employed qRT-PCR, Western blot, and immunohistochemistry to examine the expression levels of miR-193b, flap endonuclease 1 (FEN1), and autophagy-related proteins. Apoptosis was determined by flow cytometry using an Annexin V-FITC/PI apoptosis detection kit. Luciferase reporter assays confirmed the relationship between miR-193b and FEN1. Results: miR-193b was downregulated in OS compared to adjacent normal tissues (p < 0.05). miR-193b overexpression in the OS cell lines induced autophagy and apoptosis, as shown by Western blotting and flow cytometry. Knockdown of FEN1, a structure-specific nuclease overexpressed in OS tissues (p < 0.001), induced apoptosis through activation of autophagy. Luciferase reporter assays confirmed that FEN1 is a direct target of miR-193b, FEN1 knockdown reinforced miR-193b induced apoptosis. Moreover, miR-193b expression enhanced epirubicin-induced autophagy and apoptosis. Conclusion: Collectively, the results showed that miR-193b/FEN1 may serve as a novel therapeutic target for OS aimed mainly at the induction of autophagy and apoptosis. The miR-193b/FEN1 axis increased the chemosensitivity of OS cells, while activation of autophagy enhanced the anticancer effects of epirubicin.

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“…42 Sensitizing GBM cells to temozolomide via regulating autophagy has been widely reported by scholars. [68][69][70][71][72] With respect to the interplay between autophagy and AS, splicing autophagy-related genes has been reported to influence autophagy. 73,74 However, no study has reported the correlation between AS and autophagy in GBM.…”

Section: Discussionmentioning

confidence: 99%

Role of alternative splicing signatures in the prognosis of glioblastoma

Xie

Dang

et al. 2019

Cancer Medicine

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Background Increasing evidence has validated the crucial role of alternative splicing (AS) in tumors. However, comprehensive investigations on the entirety of AS and their clinical value in glioblastoma (GBM) are lacking. Methods The AS profiles and clinical survival data related to GBM were obtained from The Cancer Genome Atlas database. Univariate and multivariate Cox regression analyses were performed to identify survival‐associated AS events. A risk score was calculated, and prognostic signatures were constructed using seven different types of independent prognostic AS events, respectively. The Kaplan‐Meier estimator was used to display the survival of GBM patients. The receiver operating characteristic curve was applied to compare the predictive efficacy of each prognostic signature. Enrichment analysis and protein interactive networks were conducted using the gene symbols of the AS events to investigate important processes in GBM. A splicing network between splicing factors and AS events was constructed to display the potential regulatory mechanism in GBM. Results A total of 2355 survival‐associated AS events were identified. The splicing prognostic model revealed that patients in the high‐risk group have worse survival rates than those in the low‐risk group. The predictive efficacy of each prognostic model showed satisfactory performance; among these, the Alternate Terminator (AT) model showed the best performance at an area under the curve (AUC) of 0.906. Enrichment analysis uncovered that autophagy was the most enriched process of prognostic AS gene symbols in GBM. The protein network revealed that UBC, VHL, KCTD7, FBXL19, RNF7, and UBE2N were the core genes in GBM. The splicing network showed complex regulatory correlations, among which ELAVL2 and SYNE1_AT_78181 were the most correlated (r = −.506). Conclusions Applying the prognostic signatures constructed by independent AS events shows promise for predicting the survival of GBM patients. A splicing regulatory network might be the potential splicing mechanism in GBM.

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Inhibition of autophagy increases susceptibility of glioblastoma stem cells to temozolomide by igniting ferroptosis

Cited by 201 publications

References 65 publications

Molecular mechanisms of ferroptosis and its role in cancer therapy

Molecular mechanisms of ferroptosis and its role in cancer therapy

<p>miR-193b Increases the Chemosensitivity of Osteosarcoma Cells by Promoting FEN1-Mediated Autophagy</p>

Role of alternative splicing signatures in the prognosis of glioblastoma

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