Activated p53 in the anti-apoptotic milieu of tuberous sclerosis gene mutation induced diseases leads to cell death if thioredoxin reductase is inhibited

Abdelwahab, Elhusseiny Mohamed Mahmoud; Bovari-Biri, Judit; Smuk, Gábor; Fillinger, János; McPhail, Donald B.; Krymskaya, Vera P.; Pongrácz, Judit E.

doi:10.1007/s10495-021-01670-4

Cited by 5 publications

(6 citation statements)

References 32 publications

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“…TSC mutant cells demonstrate increased proliferation ability, reduced mitochondrial membrane potential, increased TrxR activity [ 21 , 49 ], and aberrant mitochondrial biogenesis [ 50 ]. mTOR regulates mitochondrial activity [ 51 ] and plays a central role in the relative balance of ATP generation between mitochondrial and non-mitochondrial sources.…”

Section: Discussionmentioning

confidence: 99%

“…In further support of such connections, the TSC mutation-induced deregulation of mTORC activation is linked to increased activity of the selenoprotein, i.e., thioredoxin reductase (TrxR) [21,22]. TrxR catalyzes thioredoxin reduction and consequently provides Genetic mutations or alterations in TSC1/2 have an important role not only in various cancers but also in some slow-growing neoplasms like lymphangioleiomyomatosis (LAM) [11] or angiomyolipoma (AML) [12].…”

Section: Introductionmentioning

confidence: 99%

“…In further support of such connections, the TSC mutation-induced deregulation of mTORC activation is linked to increased activity of the selenoprotein, i.e., thioredoxin reductase (TrxR) [ 21 , 22 ]. TrxR catalyzes thioredoxin reduction and consequently provides a defense mechanism against the oxidative damage caused by elevated ROS production [ 23 ].…”

Section: Introductionmentioning

confidence: 99%

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Prdx5 in the Regulation of Tuberous Sclerosis Complex Mutation-Induced Signaling Mechanisms

Bovari-Biri

Abdelwahab

Garai

et al. 2023

Cells

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(1) Background: Tuberous sclerosis complex (TSC) mutations directly affect mTORC activity and, as a result, protein synthesis. In several cancer types, TSC mutation is part of the driver mutation panel. TSC mutations have been associated with mitochondrial dysfunction, tolerance to reactive oxygen species due to increased thioredoxin reductase (TrxR) enzyme activity, tolerance to endoplasmic reticulum (ER) stress, and apoptosis. The FDA-approved drug rapamycin is frequently used in clinical applications to inhibit protein synthesis in cancers. Recently, TrxR inhibitor auranofin has also been involved in clinical trials to investigate the anticancer efficacy of the combination treatment with rapamycin. We aimed to investigate the molecular background of the efficacy of such drug combinations in treating neoplasia modulated by TSC mutations. (2) Methods: TSC2 mutant and TSC2 wild-type (WT) cell lines were exposed to rapamycin and auranofin in either mono- or combination treatment. Mitochondrial membrane potential, TrxR enzyme activity, stress protein array, mRNA and protein levels were investigated via cell proliferation assay, electron microscopy, etc. (3) Results: Auranofin and rapamycin normalized mitochondrial membrane potential and reduced proliferation capacity of TSC2 mutant cells. Database analysis identified peroxiredoxin 5 (Prdx5) as the joint target of auranofin and rapamycin. The auranofin and the combination of the two drugs reduced Prdx5 levels. The combination treatment increased the expression of heat shock protein 70, a cellular ER stress marker. (4) Conclusions: After extensive analyses, Prdx5 was identified as a shared target of the two drugs. The decreased Prdx5 protein level and the inhibition of both TrxR and mTOR by rapamycin and auranofin in the combination treatment made ER stress-induced cell death possible in TSC2 mutant cells.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

“…In further support of such connections, the TSC mutation-induced deregulation of mTORC activation is linked to increased activity of the selenoprotein, i.e., thioredoxin reductase (TrxR) [ 21 , 22 ]. TrxR catalyzes thioredoxin reduction and consequently provides a defense mechanism against the oxidative damage caused by elevated ROS production [ 23 ].…”

Section: Introductionmentioning

confidence: 99%

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Prdx5 in the Regulation of Tuberous Sclerosis Complex Mutation-Induced Signaling Mechanisms

Bovari-Biri

Abdelwahab

Garai

et al. 2023

Cells

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“…Thioredoxin reductase is known to phosphorylate and activate the p53 gene, a known tumor suppressor [36]. Consistently, and TR1 expression is increased in many carcinoma cells and tumors, including prostate [37].…”

Section: Thioredoxin Reductase: Cancer Cellular Redox and Tumorigenesismentioning

confidence: 93%

Selenium and Selenoproteins: Characterization, Potentiation, and Intracellular Emerging Roles in Cellular Physiology

Williams

2022

AJBSR

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Selenium (Se) is an essential microelement implicated in numerous physiological processes in human health and disease. From physiological roles in thyroid preservation to anti-cancer effects, the role(s) of Se continue to be an intense area of biomedical focus. The roles of Se appear to be, in part, mediated through incorporation of selenium-based proteins termed selenoproteins. In this short review, we review the known roles of these class of proteins, highlighting basic structure, cellular roles, and known implications in health and disease. The overall goal is to provide fundamental appreciation of the importance of selenium and selenoproteins in health and in disease.

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“…Last but not least, mitochondrial regulation and function of affected cell lines 75 , activation of p53 and regulation of apoptosis 76 , inflammatory mediators of the cellular microenvironment 77 , involvement of circular RNA in tumorigenesis 78 , and altered interaction between TSC2 gene proteins and high-density lipoprotein-binding proteins 79 have been considered potential therapeutic targets in TSC-related angiomyolipoma.…”

Section: Future Perspectivesmentioning

confidence: 99%

Tuberous Sclerosis Complex and the kidneys: what nephrologists need to know

Monich,

Bissler,

Barreto

2024

Braz. J. Nephrol.

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Tuberous sclerosis complex (TSC) is an autosomal dominant disease characterized by the development of hamartomas in the central nervous system, heart, skin, lungs, and kidneys and other manifestations including seizures, cortical tubers, radial migration lines, autism and cognitive disability. The disease is associated with pathogenic variants in the TSC1 or TSC2 genes, resulting in the hyperactivation of the mTOR pathway, a key regulator of cell growth and metabolism. Consequently, the hyperactivation of the mTOR pathway leads to abnormal tissue proliferation and the development of solid tumors. Kidney involvement in TSC is characterized by the development of cystic lesions, renal cell carcinoma and renal angiomyolipomas, which may progress and cause pain, bleeding, and loss of kidney function. Over the past years, there has been a notable shift in the therapeutic approach to TSC, particularly in addressing renal manifestations. mTOR inhibitors have emerged as the primary therapeutic option, whereas surgical interventions like nephrectomy and embolization being reserved primarily for complications unresponsive to clinical treatment, such as severe renal hemorrhage. This review focuses on the main clinical characteristics of TSC, the mechanisms underlying kidney involvement, the recent advances in therapy for kidney lesions, and the future perspectives.

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Activated p53 in the anti-apoptotic milieu of tuberous sclerosis gene mutation induced diseases leads to cell death if thioredoxin reductase is inhibited

Cited by 5 publications

References 32 publications

Prdx5 in the Regulation of Tuberous Sclerosis Complex Mutation-Induced Signaling Mechanisms

Prdx5 in the Regulation of Tuberous Sclerosis Complex Mutation-Induced Signaling Mechanisms

Selenium and Selenoproteins: Characterization, Potentiation, and Intracellular Emerging Roles in Cellular Physiology

Tuberous Sclerosis Complex and the kidneys: what nephrologists need to know

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