Biology subjects

Chen, W.-L.

Publications and source records attributed to Chen, W.-L..

3 recordsLinked to original sources

bioRxiv2023

Hydrogen Sulfide Coordinates Glucose Metabolism Switch through Destabilizing Tetrameric Pyruvate Kinase M2

Cancer cells reprogram their glucose metabolic pathway from oxidative phosphorylation toward aerobic glycolysis. Pyruvate kinase M2 (PKM2), which converts phosphoenolpyruvate (PEP) to pyruvate, is considered the rate-limiting enzyme involved in cancer glucose metabolism. By reducing PKM2 enzyme activity, cancer cells attain a greater fraction of glycolytic metabolites for macromolecule synthesis needed for rapid proliferation. Here we demonstrate that hydrogen sulfide (H2S) destabilizes PKM2 tetramer into dimer/monomer, leading to reduced PKM2 enzyme activity and an increase in the activation of nuclear transcriptional genes mediated by dimeric PKM2. Proteomic profiling of endogenous PKM2 reveals the occurrence of sulfhydration at cysteines, notably at cysteine 326. Blocking PKM2 sulfhydration at cysteine 326 through amino acid mutation stabilizes PKM2 tetramer and crystal structure further indicating that the tetramer organization of PKM2C326S is different from the currently known T or R states, revealing PKM2C326S as a newly identified form. The presence of a PKM2C326S mutant in cancer cells effectively rewires glucose metabolism to mitochondrial respiration, resulting in the significant inhibition of tumor growth. Collectively, PKM2 sulfhydration by H2S serves as a glucose metabolic rewiring mechanism in promoting tumorigenesis, and inhibition of PKM2 sulfhydration may be applied as a new therapeutic approach targeting cancer metabolism. One-Sentence SummaryH2S rewires glucose metabolism by destabilizing PKM2 tetramerization majorly through sulfhydration at cysteine 326 HighlightsO_LIH2S enhances PKM2 dissociation from tetramer to dimer to facilitate dimeric PKM2 nuclear translocation. C_LIO_LIH2S modifies PKM2 sulfhydration, notably at cysteine 326. C_LIO_LIThe crystal structure reveals PKM2C326S as a unique tetramer conformation. C_LIO_LIBlockage of PKM2 sulfhydration at C326 rewires cancer glucose metabolism and significantly inhibits tumor growth. C_LI

cancer biology↗

bioRxiv2021

New metabolic alterations and predictive marker pipecolic acid in sera for esophageal squamous cell carcinoma

Esophageal squamous cell carcinoma (ESCC) is a major histological subtype of esophageal cancer with dismal prognosis. Although several serum metabolomic investigations have been reported, ESCC tumor-associated metabolic alterations along with predictive biomarkers in sera were not defined. Here we enrolled 34 treatment-naive ESCC patients and collected their pre-and post-esophagectomy sera together with sera from 34 healthy volunteers for metabolomic survey. Our comprehensive analysis discerned ESCC tumor-associated metabolic alterations as represented by a panel of 12 serum metabolites. Notably, postoperative abrosia and parenteral nutrition significantly perturbed the serum metabolome. Furthermore, we performed examination using sera from carcinogen-induced mice at dysplasia and ESCC stages, and identified three ESCC tumor-associated metabolites conserved between mice and humans. Notably, among these metabolites, pipecolic acid was progressively increased in mouse sera from dysplasia to cancerization, and it could accurately discriminate between mice at dysplasia stage and healthy control mice. Furthermore, this metabolite was essential for ECSS cells to oppose oxidative stress-induced DNA damage and cell proliferation arrest. Together, this study uncovered 12 ESCC tumor-associated serum metabolites with potential for monitoring therapeutic efficacy and disease relapse, presented evidence for refining parenteral nutrition composition, and highlighted serum pipecolic acid as an attractive biomarker for prediction of ESCC tumorigenesis.

cancer biology↗

bioRxiv2019

Caenorhabditis elegans Exhibits Positive Gravitaxis

Whether or not the micro swimmer Caenorhabditis elegans senses and respond to gravity is unknown. We find that C. elegans aligns its swimming direction with that of the gravity vector (positive gravitaxis). When placed in an aqueous solution that is denser than the animals, they still orient downwards, indicating that non-uniform mass distribution and/or hydrodynamic effects are not responsible for animals downward orientation. Paralyzed worms and worms with globally disrupted sensory cilia do not change orientation as they settle in solution, indicating that gravitaxis is an active behavior that requires gravisensation. Other types of sensory driven orientation behaviors cannot explain our observed downward orientation. Like other neural behaviors, the ability to respond to gravity declines with age. Our study establishes gravitaxis in the micro swimmer C. elegans and suggests that C. elegans can be used as a genetically tractable system to study molecular and neural mechanisms of gravity sensing and orientation.\n\nSignificance StatementUnderstanding how animals respond to gravity is not only of fundamental scientific interest, but has clinical relevance, given the prevalence of postural instability in aged individuals. Determining whether C. elegans responds to gravity is important for mechanistic studies of gravity sensing in an experimentally tractable animal, for a better understanding of nematode ecology and evolution, and for studying biological effects of microgravity. Our experiments, which indicate that C. elegans senses and responds to gravity, set the stage for mechanistic studies on molecular mechanisms of gravity sensing.

neuroscience↗