Transglutaminase 2 and Ferroptosis: a new liaison?

Gagliardi, Mara; Saverio, Valentina; Rossin, Federica; D’Eletto, Manuela; Corazzari, Marco

doi:10.1038/s41420-023-01394-1

Cited by 8 publications

(8 citation statements)

References 9 publications

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“…Next, we evaluated the potential involvement of the GCH1/BH4 axis, able to mitigate the ferroptotic process [ 29 ]. Analysis of GCH1 expression in the three OS cell lines revealed a heterogeneous basal and stimulated (0.5 µM RSL3, 8 h) expression of this factor (Suppl.…”

Section: Resultsmentioning

confidence: 99%

“…Ferroptosis suppressor protein 1 (FSP1), also known as apoptosis-inducing factor mitochondrial 2 (AIFM2), or AMID, is a recently described inhibitor of ferroptosis execution, working in parallel but independent of GPX4 [ 10 , 29 ]. Therefore, to investigate the potential role of FSP1 in the resistance of OS cells to ferroptosis, we evaluated its basal levels in our panel of cells.…”

Section: Resultsmentioning

confidence: 99%

“…L34 mRNA level was used as an internal control, and the comparative Ct method (ΔΔCt) was used for relative quantification of gene expression [ 29 ].…”

Section: Methodsmentioning

confidence: 99%

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FSP1 is a predictive biomarker of osteosarcoma cells’ susceptibility to ferroptotic cell death and a potential therapeutic target

Panczyszyn,

Saverio,

Monzani

et al. 2024

Cell Death Discov.

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Human osteosarcoma (OS) is a relatively rare malignancy preferentially affecting long body bones which prognosis is often poor also due to the lack of effective therapies. Clinical management of this cancer basically relies on surgical removal of primary tumor coupled with radio/chemotherapy. Unfortunately, most osteosarcoma cells are resistant to conventional therapy, with the undergoing epithelial-mesenchymal transition (EMT) giving rise to gene expression reprogramming, thus increasing cancer cell invasiveness and metastatic potential. Alternative clinical approaches are thus urgently needed. In this context, the recently described ferroptotic cell death represents an attractive new strategy to efficiently kill cancer cells, since most chemoresistant and mesenchymal-shaped tumors display high susceptibility to pro-ferroptotic compounds. However, cancer cells have also evolved anti-ferroptotic strategies, which somehow sustain their survival upon ferroptosis induction. Indeed, here we show that osteosarcoma cell lines display heterogeneous sensitivity to ferroptosis execution, correlating with the mesenchymal phenotype, which is consistently affected by the expression of the well-known anti-ferroptotic factor ferroptosis suppressor protein 1 (FSP1). Interestingly, inhibiting the activity or expression of FSP1 restores cancer cell sensitivity to ferroptosis. Moreover, we also found that: i) AKRs might also contribute to resistance; ii) NRF2 enhances FSP1 expression upon ferroptosis induction; while iii) p53 contributes to the regulation of FSP1 basal expression in OS cells.In conclusion, FSP1 expression can potentially be used as a valuable predictive marker of OS sensitivity to ferroptosis and as a new potential therapeutic target.

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Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

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FSP1 is a predictive biomarker of osteosarcoma cells’ susceptibility to ferroptotic cell death and a potential therapeutic target

Panczyszyn,

Saverio,

Monzani

et al. 2024

Cell Death Discov.

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“…The pleiotropic nature of TG2 makes it an essential player in numerous cellular processes; it participates in cell growth and differentiation, adhesion and migration, autophagy, inflammation, tissue repair, fibrosis, extracellular matrix formation, proteostasis, apoptosis, angiogenesis, the EMT transition, and epigenetic modification [ 10 , 21 , 23 , 28 , 33 , 34 ]. The impairment of such a crucial enzyme that participates in several processes leads to different hallmarks of cancer, such as cancer progression, metastasis spread, cancer cell survival and invasion, and drug resistance.…”

Section: Tg2 In Cancermentioning

confidence: 99%

The Role of Transglutaminase 2 in Cancer: An Update

Zaltron,

Vianello,

Ruzza

et al. 2024

IJMS

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Transglutaminase type 2 (TG2) is the most ubiquitously expressed and well characterized member of the transglutaminase family. It is a ubiquitous multifunctional enzyme implicated in the regulation of several cellular pathways that support the survival, death, and general homeostasis of eukaryotic cells. Due to its multiple localizations both inside and outside the cell, TG2 participates in the regulation of many crucial intracellular signaling cascades in a tissue- and cell-specific manner, making this enzyme an important player in disease development and progression. Moreover, TG2 is capable of modulating the tumor microenvironment, a process of dynamic tissue remodeling and biomechanical events, resulting in changes which influence tumor initiation, growth, and metastasis. Even if generally related to the Ca2+-dependent post-translational modification of proteins, a number of different biological functions have been ascribed to TG2, like those of a peptide isomerase, protein kinase, guanine nucleotide binder, and cytosolic–nuclear translocator. With respect to cancer, TG2′s role is controversial and highly debated; it has been described both as an anti- and pro-apoptotic factor and is linked to all the processes of tumorigenesis. However, numerous pieces of evidence support a tissue-specific role of TG2 so that it can assume both oncogenic and tumor-suppressive roles.

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“…В ряде работ показано участие TG2 в созревании аутофагосом, в то время как малейшее колебание внутриклеточных параметров может привести к функциональным изменениям активности TG2 и, как следствие, к нарушению баланса в сторону клеточной гибели [49,50,93]. Наконец, недавние исследования демонстрируют участие TG2 в еще одном типе клеточной гибели -ферроптозе, характеризующемся токсичным железозависимым накоплением перекисей липидов, что еще больше подчеркивает значимость изучения и понимания всех молекулярных процессов, в которые вовлечена TG2 [94].…”

Section: Fig 2 Effect Of Transglutaminase 2 (Tg2) On Autophagy / Apop...unclassified

The role of transglutaminase 2 in regulation of the balance between autophagy and apoptosis in tumor cells

Gnennaya,

Semenov,

Barlev

2023

Usp. mol. onkol

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In normal tissue, cellular homeostasis is largely driven by two catabolic pathways: apoptosis and autophagy. Apoptosis, or programmed cell death, is regulated by pro-apoptotic factors, and promotes the removal of problematic cells. Autophagy, which in turn includes three forms: macro-, micro-, and chaperone-mediated autophagy, can promote both cell survival by selectively removing potentially apoptosis-inducing factors and raising the threshold of stress required for the induction of cell death. Recently, evidence has been accumulating suggesting the existence of common molecular pathways between autophagy and apoptosis, as well as the influence of the extracellular matrix on these processes. One of the important enzymes involved in the coordination and regulation of these processes is transglutaminase 2 (TG2). Different types of TG2 activities are involved in maintaining the dynamic balance between extracellular matrix and intracellular autophagy/apoptosis processes, while dysregulation of these processes may contribute to the pathogenesis of various human diseases, including oncogenesis. For example, TG2 can promote the degradation of pro-apoptotic proteins and the survival of renal cell carcinoma cells under nutrient-deficient conditions by modulating the autophagy process. In cells of various tissues deprived of TG2, aggregates of ubiquitinated proteins and damaged mitochondria are observed, which in turn induces proteotoxic stress and cell death. conversely, the transamidase activity of TG2 was observed to inhibit anti-apoptotic signaling in a human leukemic monocytic lymphoma model. In the present review, a number of important functions of TG2 in oncogenesis are described, along with the dual role of TG2 in modulating such opposite processes as cell survival and cell death.

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Transglutaminase 2 and Ferroptosis: a new liaison?

Cited by 8 publications

References 9 publications

FSP1 is a predictive biomarker of osteosarcoma cells’ susceptibility to ferroptotic cell death and a potential therapeutic target

FSP1 is a predictive biomarker of osteosarcoma cells’ susceptibility to ferroptotic cell death and a potential therapeutic target

The Role of Transglutaminase 2 in Cancer: An Update

The role of transglutaminase 2 in regulation of the balance between autophagy and apoptosis in tumor cells

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