LASS5 Interacts with SDHB and Synergistically Represses p53 and p21 Activity

Jiang, Zhe; Li, F; Wan, Ying; Han, Zhe; Yuan, Wenwen; Cao, Lihua; Deng, Yun; Peng, Xiaoqian; Chen, F; Fan, Xueli; Liu, X; Dai, G; Wang, Y; Qing-jun, Zeng; Shi, Yan; Zhou, Ziwen; Chen, Y; Xu, Wei; Luo, Sheng; Chen, S; Ye, X; Mo, Xiaoning; Wu, Xiushan; Li, Y

doi:10.2174/1566524016666160607090012

Cited by 7 publications

(3 citation statements)

References 43 publications

(69 reference statements)

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“…33 ). For example, treatment of HCT116 cells with exogenous C 16 -ceramide transcriptionally upregulated p53 34 , while CerS5 expression in COS-7 cells repressed the p53 reporter activity 35 . Several studies demonstrated indirect effect of ceramide on p53, through additional mediators such as PP2A, AMPK, and Bcl-2 36 , 37 , but the mechanistic studies of the direct ceramide effect on p53 are still missing.…”

Section: Discussionmentioning

confidence: 99%

C16-ceramide is a natural regulatory ligand of p53 in cellular stress response

Fekry

Jeffries

Esmaeilniakooshkghazi

et al. 2018

Nat Commun

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Ceramides are important participants of signal transduction, regulating fundamental cellular processes. Here we report the mechanism for activation of p53 tumor suppressor by C16-ceramide. C16-ceramide tightly binds within the p53 DNA-binding domain (Kd ~ 60 nM), in close vicinity to the Box V motif. This interaction is highly selective toward the ceramide acyl chain length with its C10 atom being proximal to Ser240 and Ser241. Ceramide binding stabilizes p53 and disrupts its complex with E3 ligase MDM2 leading to the p53 accumulation, nuclear translocation and activation of the downstream targets. This mechanism of p53 activation is fundamentally different from the canonical p53 regulation through protein–protein interactions or posttranslational modifications. The discovered mechanism is triggered by serum or folate deprivation implicating it in the cellular response to nutrient/metabolic stress. Our study establishes C16-ceramide as a natural small molecule activating p53 through the direct binding.

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Section: Discussionmentioning

confidence: 99%

C16-ceramide is a natural regulatory ligand of p53 in cellular stress response

Fekry

Jeffries

Esmaeilniakooshkghazi

et al. 2018

Nat Commun

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“…Another study where data from a reverse-phase protein microarray using epithelium-enriched, human CRC tissue samples were used revealed that high CerS5 protein expression is associated with the autophagy-regulating protein signaling network, in contrast to low CerS5 levels that are associated with an apoptosis-related proteomic network [ 177 ]. In human neuroglioma tissue, elevated expressions of CerS5 mRNA and protein levels were observed when compared with normal nervous ganglion tissue [ 178 ]. These studies suggest the correlation between high CerS5 expression and tumor cell proliferation and cancer progression in CRC, breast cancer, and other malignancies.…”

Section: Ceramide Synthasesmentioning

confidence: 99%

Natural Products and Small Molecules Targeting Cellular Ceramide Metabolism to Enhance Apoptosis in Cancer Cells

Afrin,

Mateen,

Oman

et al. 2023

Cancers

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Molecular targeting strategies have been used for years in order to control cancer progression and are often based on targeting various enzymes involved in metabolic pathways. Keeping this in mind, it is essential to determine the role of each enzyme in a particular metabolic pathway. In this review, we provide in-depth information on various enzymes such as ceramidase, sphingosine kinase, sphingomyelin synthase, dihydroceramide desaturase, and ceramide synthase which are associated with various types of cancers. We also discuss the physicochemical properties of well-studied inhibitors with natural product origins and their related structures in terms of these enzymes. Targeting ceramide metabolism exhibited promising mono- and combination therapies at preclinical stages in preventing cancer progression and cemented the significance of sphingolipid metabolism in cancer treatments. Targeting ceramide-metabolizing enzymes will help medicinal chemists design potent and selective small molecules for treating cancer progression at various levels.

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“…The increased CerS5 expression is negatively correlated with the poor prognosis of CRC patients ( 17 ). Jiang et al reported that the levels of CerS5 mRNA and protein in human neuroglioma tissues were significantly higher than those in normal nervous ganglion tissues ( 18 ). And the overexpression of CerS5 has been reported to trigger cellular apoptosis via the promotion of ceramide up-regulation following hypoxia or reoxygenation ( 19 ).…”

Section: Introductionmentioning

confidence: 99%

High expression of ceramide synthase 5 predicts a poor prognosis in gastric cancer

Zhang¹,

Wang²,

Li³

et al. 2022

Transl Cancer Res TCR

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Background: Gastric cancer is one of the most common malignant tumors worldwide. Ceramide synthase 5 (CerS5) is a member of the CerS family. Emerging evidence has shown that overexpressed CerS5 is correlated with the poor prognosis of cancer patients. However, the role of CerS5 in gastric cancer remains unclear. The aim of this study is to delineate the relevance of CerS5 levels to gastric cancer.Methods: The expression level of CerS5 was determined by immunohistochemistry, and the survival data of gastric cancer patients were obtained by regular follow-up. The gene expression profile of CerS5 and corresponding clinical features of gastric cancer patients from public databases were obtained fromThe Cancer Genome Atlas (TCGA) and Asian Cancer Research Group (ACRG). The Chi-square test and Fisher's exact test were used to determine the correlation between CerS5 expression and clinicopathological characteristics of gastric cancer patients. Univariate and multivariate Cox regression analyses were used to determine the independent prognostic factors of patients with gastric cancer.Results: Immunohistochemistry (IHC) staining indicated that CerS5 is overexpressed in gastric cancer tissues and metastatic lymph nodes. The levels of CerS5 were correlated with tumor location and carbohydrate antigen 50 (CA50). Moreover, the increased CerS5 levels were significantly correlated with poor prognosis in gastric cancer patients from the ACRG and our institute, but not TCGA, suggesting that CerS5 is probably a prognosis marker of gastric cancer for the Asian population. Finally, univariate and multivariate analyses showed that high expression of CerS5 is an independent factor of poor prognosis for gastric cancer patients.Conclusions: CerS5 is universally overexpressed in gastric cancer tissues and is an independent factor of poor prognosis for gastric cancer patients.

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LASS5 Interacts with SDHB and Synergistically Represses p53 and p21 Activity

Cited by 7 publications

References 43 publications

C16-ceramide is a natural regulatory ligand of p53 in cellular stress response

C16-ceramide is a natural regulatory ligand of p53 in cellular stress response

Natural Products and Small Molecules Targeting Cellular Ceramide Metabolism to Enhance Apoptosis in Cancer Cells

High expression of ceramide synthase 5 predicts a poor prognosis in gastric cancer

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