Gambogic acid suppresses the pentose phosphate pathway by covalently inhibiting 6PGD protein in cancer cells

Zhu, Yinhua; Zhang, Qianyu; Ma, Ang; Zhang, Ying; Wang, Chen; Gao, Peng; Guo, Qiuyan; Xia, Fei; Tang, Huan; Xu, Chengchao; Wang, Jigang

doi:10.1039/d2cc03069a

Cited by 4 publications

(1 citation statement)

References 23 publications

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“…The same amount of protein was taken for reduction with dithiothreitol (DTT) and reaction with IAA. The proteins were then digested with trypsin overnight at 37 °C [ 23 ]. After digestion, the peptides were desalted and spin-drying for LC-MS/MS analysis.…”

Section: Bio-layer Interferometry (Bli) Assaymentioning

confidence: 99%

Chemoproteomics-based profiling reveals potential antimalarial mechanism of Celastrol by disrupting spermidine and protein synthesis

Gao,

Wang,

Tang

et al. 2024

Cell Commun Signal

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Background Malaria remains a global health burden, and the emergence and increasing spread of drug resistance to current antimalarials poses a major challenge to malaria control. There is an urgent need to find new drugs or strategies to alleviate this predicament. Celastrol (Cel) is an extensively studied natural bioactive compound that has shown potentially promising antimalarial activity, but its antimalarial mechanism remains largely elusive. Methods We first established the Plasmodium berghei ANKA-infected C57BL/6 mouse model and systematically evaluated the antimalarial effects of Cel in conjunction with in vitro culture of Plasmodium falciparum. The potential antimalarial targets of Cel were then identified using a Cel activity probe based on the activity-based protein profiling (ABPP) technology. Subsequently, the antimalarial mechanism was analyzed by integrating with proteomics and transcriptomics. The binding of Cel to the identified key target proteins was verified by a series of biochemical experiments and functional assays. Results The results of the pharmacodynamic assay showed that Cel has favorable antimalarial activity both in vivo and in vitro. The ABPP-based target profiling showed that Cel can bind to a number of proteins in the parasite. Among the 31 identified potential target proteins of Cel, PfSpdsyn and PfEGF1-α were verified to be two critical target proteins, suggesting the role of Cel in interfering with the de novo synthesis of spermidine and proteins of the parasite, thus exerting its antimalarial effects. Conclusions In conclusion, this study reports for the first time the potential antimalarial targets and mechanism of action of Cel using the ABPP strategy. Our work not only support the expansion of Cel as a potential antimalarial agent or adjuvant, but also establishes the necessary theoretical basis for the development of potential antimalarial drugs with pentacyclic triterpenoid structures, as represented by Cel.

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Section: Bio-layer Interferometry (Bli) Assaymentioning

confidence: 99%

Chemoproteomics-based profiling reveals potential antimalarial mechanism of Celastrol by disrupting spermidine and protein synthesis

Gao,

Wang,

Tang

et al. 2024

Cell Commun Signal

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Triptolide induces apoptosis and cytoprotective autophagy by ROS accumulation via directly targeting peroxiredoxin 2 in gastric cancer cells

Chen,

Zhong,

Song

et al. 2024

Cancer Letters

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Microplastics exposure causes the senescence of human lung epithelial cells and mouse lungs by inducing ROS signaling

Jin,

Zhang,

Tang

et al. 2024

Environment International

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Gambogic acid suppresses the pentose phosphate pathway by covalently inhibiting 6PGD protein in cancer cells

Abstract: Whether the anticancer activity of Gambogic acid is achieved by regulating cellular metabolic process remains unclear. Here we reported that Gambogic acid suppresses PPP pathway by covalently inhibiting 6PGD protein....

Cited by 4 publications

References 23 publications

Chemoproteomics-based profiling reveals potential antimalarial mechanism of Celastrol by disrupting spermidine and protein synthesis

Chemoproteomics-based profiling reveals potential antimalarial mechanism of Celastrol by disrupting spermidine and protein synthesis

Triptolide induces apoptosis and cytoprotective autophagy by ROS accumulation via directly targeting peroxiredoxin 2 in gastric cancer cells

Microplastics exposure causes the senescence of human lung epithelial cells and mouse lungs by inducing ROS signaling

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