The mevalonate coordinates energy input and cell proliferation

Gong, Li; Xiao, Yi; Xia, Fan; Wu, Pei; Zhao, Tingting; Xie, Shulin; Wang, Ran; Wen, Qiaocheng; Zhou, Wei; Xu, Huilan; Zhu, Lingyan; Zheng, Zeqi; Yang, Tianlun; Chen, Zihua; Duan, Qiong

doi:10.1038/s41419-019-1544-y

Cited by 33 publications

(27 citation statements)

References 38 publications

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“…The SREBF2-regulated mevalonate pathway was one of the p53—inhibited pathways with highest positive z -score (Table 1 ), suggesting up-regulation due to absence of p53 inhibitory control. Mevalonate pathway—which is involved in biosynthesis of sterols and regulation of energy metabolism—evokes pro-survival signaling and is up-regulated in various cancers (Gong 2019 ; Guerra et al 2021 ). The above results confirm that POX silencing in MCF-7 iPOX cells leads to down-regulation of p53 inhibitory control over cellular survival and up-regulation of pro-survival pathways.…”

Section: Discussionmentioning

confidence: 99%

Proline oxidase silencing inhibits p53-dependent apoptosis in MCF-7 breast cancer cells

et al. 2021

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Proline oxidase (POX) is mitochondrial proline-degrading enzyme of dual apoptosis/survival function. POX expression and proline availability are considered an underlying mechanism for differential POX functions. The mechanism for POX-dependent regulation of cell death/survival was studied in wild-type (MCF-7WT) and shRNA POX-silenced breast cancer cells (MCF-7iPOX). Proline concentration and proteomic analyses were determined by LC/MS/QTOF and LC/MS/ORBITRA, respectively. Inhibition of collagen biosynthesis (proline utilizing process) by 2-methoxyestradiol (2ME) contributed to induction of apoptosis in MCF-7WT cells, as detected by increase in the expression of active caspase-3, -9 and p53. The process was not shown in MCF-7iPOX. In MCF-7iPOX cells prolidase activity and expression as well as proline concentration were drastically increased, compared to MCF-7WT cells. Down-regulation of p53 in MCF-7iPOX cells was corroborated by proteomic analysis showing decrease in the expression of p53-related proteins. The mechanism for down-regulation of p53 expression in MCF-7iPOX cells was found at the level of p53–PEPD complex formation that was counteracted by hydrogen peroxide treatment. In this study, we found that silencing POX modulate pro-survival phenotype of MCF-7 cells and suggest that the mechanism of this process undergoes through down-regulation of p53-dependent signaling.

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Section: Discussionmentioning

confidence: 99%

Proline oxidase silencing inhibits p53-dependent apoptosis in MCF-7 breast cancer cells

et al. 2021

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“…Statins inhibit 3-hydroxy-3-methylglutaryl-CoA reductase, the rate-limiting enzyme of the mevalonate pathway. It has been proposed that statins induce tumor-specific apoptosis through mitochondrial apoptotic signaling pathways, which are activated by the suppression of mevalonate or geranylgeranyl pyrophosphate biosynthesis ( Gong et al, 2019 ). These drugs have shown the ability to limit migration in cultured tumor cells, which some researchers have speculated could translate to slowing tumor invasion in vitro ( Bababeygy et al, 2009 ).…”

Section: Opportunities To Target Metabolism In Gbm As a Way Of Targeting Gbm Invasionmentioning

confidence: 99%

Metabolic Drivers of Invasion in Glioblastoma

Garcia

Jain

Aghi

2021

Front. Cell Dev. Biol.

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Glioblastoma is a primary malignant brain tumor with a median survival under 2 years. The poor prognosis glioblastoma caries is largely due to cellular invasion, which enables escape from resection, and drives inevitable recurrence. While most studies to date have focused on pathways that enhance the invasiveness of tumor cells in the brain microenvironment as the primary driving forces behind GBM’s ability to invade adjacent tissues, more recent studies have identified a role for adaptations in cellular metabolism in GBM invasion. Metabolic reprogramming allows invasive cells to generate the energy necessary for colonizing surrounding brain tissue and adapt to new microenvironments with unique nutrient and oxygen availability. Historically, enhanced glycolysis, even in the presence of oxygen (the Warburg effect) has dominated glioblastoma research with respect to tumor metabolism. More recent global profiling experiments, however, have identified roles for lipid, amino acid, and nucleotide metabolism in tumor growth and invasion. A thorough understanding of the metabolic traits that define invasive GBM cells may provide novel therapeutic targets for this devastating disease. In this review, we focus on metabolic alterations that have been characterized in glioblastoma, the dynamic nature of tumor metabolism and how it is shaped by interaction with the brain microenvironment, and how metabolic reprogramming generates vulnerabilities that may be ripe for exploitation.

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“…These potential effectors include stress fibre actin, cyclin D1 and cyclin-dependent kinase inhibitors p21 and p27 [ 20 , 54 ]. Moreover, Rho-independent regulators of YAP, such as PDZ-binding kinase, IGF-1 and Wnt signallings [ 54 – 56 ], could also contribute to the cytoprotection of GGOH. Further studies are needed to advance our knowledge about the mechanisms controlling GGOH effect against ZA cytotoxicity.…”

Section: Discussionmentioning

confidence: 99%

Geranylgeraniol prevents zoledronic acid-mediated reduction of viable mesenchymal stem cells via induction of Rho-dependent YAP activation

2021

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Long-term use of zoledronic acid (ZA) increases the risk of medication-related osteonecrosis of the jaw (MRONJ). This may be attributed to ZA-mediated reduction of viable mesenchymal stem cells (MSCs). ZA inhibits protein geranylgeranylation, thus suppressing cell viability and proliferation. Geranylgeraniol (GGOH), which is a naturally found intermediate compound in the mevalonate pathway, has positive effects against ZA. However, precise mechanisms by which GGOH may help preserve stem cell viability against ZA are not fully understood. The objective of this study was to investigate the cytoprotective mechanisms of GGOH against ZA. The results showed that while ZA dramatically decreased the number of viable MSCs, GGOH prevented this negative effect. GGOH-rescued ZA-exposed MSCs formed mineralization comparable to that produced by normal MSCs. Mechanistically, GGOH preserved the number of viable MSCs by its reversal of ZA-mediated Ki67 + MSC number reduction, cell cycle arrest and apoptosis. Moreover, GGOH prevented ZA-suppressed RhoA activity and YAP activation. The results also established the involvement of Rho-dependent YAP and YAP-mediated CDK6 in the cytoprotective ability of GGOH against ZA. In conclusion, GGOH preserves a pool of viable MSCs with osteogenic potency against ZA by rescuing the activity of Rho-dependent YAP activation, suggesting GGOH as a promising agent and YAP as a potential therapeutic target for MRONJ.

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The mevalonate coordinates energy input and cell proliferation

Cited by 33 publications

References 38 publications

Proline oxidase silencing inhibits p53-dependent apoptosis in MCF-7 breast cancer cells

Proline oxidase silencing inhibits p53-dependent apoptosis in MCF-7 breast cancer cells

Metabolic Drivers of Invasion in Glioblastoma

Geranylgeraniol prevents zoledronic acid-mediated reduction of viable mesenchymal stem cells via induction of Rho-dependent YAP activation

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