Role of sestrins in metabolic and aging-related diseases

Fang, Huan; Shi, Xiangxiang; Jiang, Wan; Zhong, Xiaolin

doi:10.1007/s10522-023-10053-y

Cited by 3 publications

(1 citation statement)

References 108 publications

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“…The aberrant accumulation of ROS affects genomic stability and the microenvironment and disrupts cellular homeostasis leading to the loss of normal cellular functions. Molecular chaperones that regulate stress response as a first line of defense by attenuating ROS and facilitating the correct conformation and intracellular localization of proteins have been considered therapeutic targets for age-related metabolic diseases and cancer [ 7 , 8 ]. The latter is commonly associated with the overexpression of stress chaperones (including HSP40, HSP60, HSP70, and HSP90) that play a substantial role in hyper-proliferation and anti-apoptotic characteristics of tumors and hence are also used as tumor biomarkers [ 9 ].…”

Section: Introductionmentioning

confidence: 99%

Mixtures of Three Mortaparibs with Enhanced Anticancer, Anti-Migration, and Antistress Activities: Molecular Characterization in p53-Null Cancer Cells

Wadhwa,

Yang,

Meidinna

et al. 2024

Cancers

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Mortalin, a member of the Hsp70 family of proteins, is commonly enriched in many types of cancers. It promotes carcinogenesis and metastasis in multiple ways of which the inactivation of the tumor suppressor activity of p53 has been firmly established. The downregulation of mortalin and/or disruption of mortalin–p53 interactions by small molecules has earlier been shown to activate p53 function yielding growth arrest/apoptosis in cancer cells. Mortaparibs (Mortaparib, MortaparibPlus, and MortaparibMild) are chemical inhibitors of mortalin isolated by cell-based two-way screening involving (i) a shift in the mortalin staining pattern from perinuclear (characteristics of cancer cells) to pancytoplasmic (characteristics of normal cells) and (ii) the nuclear enrichment of p53. They have similar structures and also cause the inhibition of PARP1 and hence were named Mortaparibs. In the present study, we report the anticancer and anti-metastasis activity of MortaparibMild (4-[(4-amino-5-thiophen-2-yl-1,2,4-triazol-3-yl)sulfanylmethyl]-N-(4-methoxyphenyl)-1,3-thiazol-2-amine) in p53-null cells. By extensive molecular analyses of cell proliferation, growth arrest, and apoptosis pathways, we demonstrate that although it causes relatively weaker cytotoxicity compared to Mortaparib and MortaparibPlus, its lower concentrations were equally potent to inhibit cell migration. We developed combinations (called MortaparibMix-AP, MortaparibMix-AM, and MortaparibMix-AS) consisting of different ratios of three Mortaparibs for specifically enhancing their anti-proliferation, anti-migration, and antistress activities, respectively. Based on the molecular analyses of control and treated cells, we suggest that the three Mortaparibs and their mixtures may be considered for further laboratory and clinical studies validating their use for the treatment of cancer as well as prevention of its relapse and metastasis.

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Section: Introductionmentioning

confidence: 99%

Mixtures of Three Mortaparibs with Enhanced Anticancer, Anti-Migration, and Antistress Activities: Molecular Characterization in p53-Null Cancer Cells

Wadhwa,

Yang,

Meidinna

et al. 2024

Cancers

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Redox signaling and modulation in ageing

Atayik

Çakatay

2023

Biogerontology

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Sestrin2 and Sestrin3 protect spermatogenesis against heat-induced meiotic defects

Chen,

Wang,

Wang

et al. 2024

Biology of Reproduction

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Heat stress induces testicular oxidative stress, impairs spermatogenesis, and increases the risk of male infertility. Recent studies have highlighted the antioxidative properties of the Sestrins family in reducing cellular oxidative damage. However, the role of Sestrins (Sestrin1, 2, and 3) in the testicular response to heat stress remains unclear. Here, we found that Sestrin2 and 3 were highly expressed in the testis relative to Sestrin1. Then, the Sestrin2−/− and Sestrin3−/− mice were generated by CRISPR/Cas9 to investigate the role of them on spermatogenesis after heat stress. Our data showed that Sestrin2−/− and Sestrin3−/− mice testes exhibited more severe damage manifested by exacerbated loss of germ cells and higher levels of oxidative stress as compared to wild-type counterparts after heat stress. Notably, Sestrin2−/− and Sestrin3−/− mice underwent a remarkable increase in heat-induced spermatocyte apoptosis than that of controls. Furthermore, the transcriptome landscape of spermatocytes and chromosome spreading showed that loss of Sestrin2 and Sestrin3 exacerbated meiotic failure by compromising DNA double-strand breaks repair after heat stress. Taken together, our work demonstrated a critical protective function of Sestrin2 and Sestrin3 in mitigating the impairments of spermatogenesis against heat stress.

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Role of sestrins in metabolic and aging-related diseases

Cited by 3 publications

References 108 publications

Mixtures of Three Mortaparibs with Enhanced Anticancer, Anti-Migration, and Antistress Activities: Molecular Characterization in p53-Null Cancer Cells

Mixtures of Three Mortaparibs with Enhanced Anticancer, Anti-Migration, and Antistress Activities: Molecular Characterization in p53-Null Cancer Cells

Redox signaling and modulation in ageing

Sestrin2 and Sestrin3 protect spermatogenesis against heat-induced meiotic defects

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