Dataset Information

LDHA Suppression Altering Metabolism Inhibits Tumor Progress by an Organic Arsenical.

ABSTRACT: Based on the potential therapeutic value in targeting metabolism for the treatment of cancer, an organic arsenical PDT-BIPA was fabricated, which exerted selective anti-cancer activity in vitro and in vivo via targeting lactate dehydrogenase A (LDHA) to remodel the metabolic pathway. In details, the precursor PDT-BIPA directly inhibited the function of LDHA and converted the glycolysis to oxidative phosphorylation causing ROS burst and mitochondrial dysfunction. PDT-BIPA also altered several gene expression, such as HIF-1? and C-myc, to support the metabolic remodeling. All these changes lead to caspase family-dependent cell apoptosis in vivo and in vitro without obvious side effect. Our results provided this organic arsenical precursor as a promising anticancer candidate and suggested metabolism as a target for cancer therapies.

SUBMITTER: Liu YJ

PROVIDER: S-EPMC6940739 | biostudies-literature | 2019 Dec

REPOSITORIES: biostudies-literature

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LDHA Suppression Altering Metabolism Inhibits Tumor Progress by an Organic Arsenical.

Liu Yu-Jiao YJ Fan Xiao-Yang XY Wang An-Dong AD Xia Yin-Zheng YZ Fu Wen-Rong WR Liu Jun-Yi JY Jiang Feng-Lei FL Liu Yi Y

International journal of molecular sciences 20191211 24

Based on the potential therapeutic value in targeting metabolism for the treatment of cancer, an organic arsenical PDT-BIPA was fabricated, which exerted selective anti-cancer activity in vitro and in vivo via targeting lactate dehydrogenase A (LDHA) to remodel the metabolic pathway. In details, the precursor PDT-BIPA directly inhibited the function of LDHA and converted the glycolysis to oxidative phosphorylation causing ROS burst and mitochondrial dysfunction. PDT-BIPA also altered several gen ...[more]

PMID: 31835667

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Project description:ZipA is essential for cell division in Escherichia coli, acting early in the process to anchor polymers of FtsZ to the cytoplasmic membrane. Along with FtsA, FtsZ and ZipA form a proto-ring at midcell that recruits additional proteins to eventually build the division septum. Cells carrying the thermosensitive zipA1 allele divide fairly normally at 30°C in rich medium but cease dividing at temperatures above 34°C, forming long filaments. In a search for suppressors of the zipA1 allele, we found that deletions of specific genes involved in amino acid biosynthesis could partially rescue cell growth and division at 34°C or 37°C but not at 42°C. Notably, although a diverse group of amino acid biosynthesis gene deletions could partially rescue the growth of zipA1 cells at 34°C, only deletions of genes related to the biosynthesis of threonine, glycine, serine, and methionine could rescue growth at 37°C. Adding exogenous pyridoxal 5-phosphate (PLP), a cofactor for many of the enzymes affected by this study, partially suppressed zipA1 mutant thermosensitivity. For many of the deletions, PLP had an additive rescuing effect on the zipA1 mutant. Moreover, added PLP partially suppressed the thermosensitivity of ftsQ and ftsK mutants and weakly suppressed an ftsI mutant, but it failed to suppress ftsA or ftsZ thermosensitive mutants. Along with the ability of a deletion of metC to partially suppress the ftsK mutant, our results suggest that perturbations of amino acid metabolic pathways, particularly those that redirect the flow of carbon away from the synthesis of threonine, glycine, or methionine, are able to partially rescue some cell division defects.IMPORTANCE Cell division of bacteria, such as Escherichia coli, is essential for their successful colonization. It is becoming increasingly clear that nutritional status and central metabolism can affect bacterial size and shape; for example, a metabolic enzyme (OpgH) can moonlight as a regulator of FtsZ, an essential cell division protein. Here, we demonstrate a link between amino acid metabolism and ZipA, another essential cell division protein that binds directly to FtsZ and tethers it to the cytoplasmic membrane. Our evidence suggests that altering flux through the methionine-threonine-glycine-serine pathways and supplementing with the enzyme cofactor pyridoxal-5-phosphate can partially compensate for an otherwise lethal defect in ZipA, as well as several other cell division proteins.

Dataset Information

LDHA Suppression Altering Metabolism Inhibits Tumor Progress by an Organic Arsenical.

Publications

LDHA Suppression Altering Metabolism Inhibits Tumor Progress by an Organic Arsenical.

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