Phosphoglycerate dehydrogenase(PHGDH)has emerged as a crucial factor in macromolecule synthesis,neutralizing oxidative stress,and regulating methylation reactions in cancer cells,lymphocytes,and endothelial cells.Howe...Phosphoglycerate dehydrogenase(PHGDH)has emerged as a crucial factor in macromolecule synthesis,neutralizing oxidative stress,and regulating methylation reactions in cancer cells,lymphocytes,and endothelial cells.However,the role of PHGDH in tumor-associated macrophages(TAMs)is poorly understood.Here,we found that the T helper 2(Th2)cytokine interleukin-4 and tumor-conditioned media upregulate the expression of PHGDH in macrophages and promote immunosuppressive M2 macrophage activation and proliferation.Loss of PHGDH disrupts cellular metabolism and mitochondrial respiration,which are essential for immunosuppressive macrophages.Mechanistically,PHGDH-mediated serine biosynthesis promotesα-ketoglutarate production,which activates mTORC1 signaling and contributes to the maintenance of an M2-like macrophage phenotype in the tumor microenvironment.Genetic ablation of PHGDH in macrophages from tumor-bearing mice results in attenuated tumor growth,reduced TAM infiltration,a phenotypic shift of M2-like TAMs toward an M1-like phenotype,downregulated PD-L1 expression and enhanced antitumor T-cell immunity.Our study provides a strong basis for further exploration of PHGDH as a potential target to counteract TAM-mediated immunosuppression and hinder tumor progression.展开更多
Cancer stem cells(CSCs)play a pivotal role in tumor initiation,proliferation,metastasis,drug resistance,and recurrence.Consequently,targeting CSCs has emerged as a promising avenue for cancer therapy.Recently,3-phosph...Cancer stem cells(CSCs)play a pivotal role in tumor initiation,proliferation,metastasis,drug resistance,and recurrence.Consequently,targeting CSCs has emerged as a promising avenue for cancer therapy.Recently,3-phosphoglycerate dehydrogenase(PHGDH)has been identified as being intricately associated with the regulation of numerous cancer stem cells.Yet,reports detailing the functional regulators of PHGDH that can mitigate the stemness across cancer types are limited.In this study,the novel“molecular glue”LXH-3-71 was identified,and it robustly induced degradation of PHGDH,thereby modulating the stemness of colorectal cancer cells(CRCs)both in vitro and in vivo.Remarkably,LXH-3-71 was observed to form a dynamic chimera,between PHGDH and the DDB1-CRL E3 ligase.These insights not only elucidate the anti-CSCs mechanism of the lead compound but also suggest that degradation of PHGDH may be a more viable therapeutic strategy than the development of PHGDH inhibitors.Additionally,compound LXH-3-71 was leveraged as a novel ligand for the DDB1-CRL E3 ligase,facilitating the development of new PROTAC molecules targeting EGFR and CDK4 degradation.展开更多
At the forefront of cancer research is the rapidly evolving understanding of metabolic reprogramming within cancer cells.The expeditious adaptation to metabolic inhibition allows cells to evolve and acquire resistance...At the forefront of cancer research is the rapidly evolving understanding of metabolic reprogramming within cancer cells.The expeditious adaptation to metabolic inhibition allows cells to evolve and acquire resistance to targeted treatments,which makes therapeutic exploitation complex but achievable.3-phosphoglycerate dehydrogenase(PHGDH)is the rate-limiting enzyme of de novo serine biosynthesis and is highly expressed in a variety of cancers,including breast cancer,melanoma,and Ewing’s sarcoma.This review will investigate the role of PHGDH in normal biological processes,leading to the role of PHGDH in the progression of cancer.With an understanding of the molecular mechanisms by which PHGDH expression advances cancer growth,we will highlight the known mechanisms of resistance to cancer therapeutics facilitated by PHGDH biology and identify avenues for combatting PHGDH-driven resistance with inhibitors of PHGDH to allow for the development of effective metabolic therapies.展开更多
Serine metabolism is reportedly involved in immune cell functions, but whether and how serine metabolism regulates macrophage polarization remain largely unknown. Here, we show that suppressing serine metabolism, eith...Serine metabolism is reportedly involved in immune cell functions, but whether and how serine metabolism regulates macrophage polarization remain largely unknown. Here, we show that suppressing serine metabolism, either by inhibiting the activity of the key enzyme phosphoglycerate dehydrogenase in the serine biosynthesis pathway or by exogenous serine and glycine restriction, robustly enhances the polarization of interferon-γ-activated macrophages (M(IFN-γ)) but suppresses that of interleukin-4-activated macrophages (M(IL-4)) both in vitro and in vivo. Mechanistically, serine metabolism deficiency increases the expression of IGF1 by reducing the promoter abundance of S-adenosyl methionine-dependent histone H3 lysine 27 trimethylation. IGF1 then activates the p38-dependent JAK–STAT1 axis to promote M(IFN-γ) polarization and suppress STAT6-mediated M(IL-4) activation. This study reveals a new mechanism by which serine metabolism orchestrates macrophage polarization and suggests the manipulation of serine metabolism as a therapeutic strategy for macrophage-mediated immune diseases.展开更多
文摘Phosphoglycerate dehydrogenase(PHGDH)has emerged as a crucial factor in macromolecule synthesis,neutralizing oxidative stress,and regulating methylation reactions in cancer cells,lymphocytes,and endothelial cells.However,the role of PHGDH in tumor-associated macrophages(TAMs)is poorly understood.Here,we found that the T helper 2(Th2)cytokine interleukin-4 and tumor-conditioned media upregulate the expression of PHGDH in macrophages and promote immunosuppressive M2 macrophage activation and proliferation.Loss of PHGDH disrupts cellular metabolism and mitochondrial respiration,which are essential for immunosuppressive macrophages.Mechanistically,PHGDH-mediated serine biosynthesis promotesα-ketoglutarate production,which activates mTORC1 signaling and contributes to the maintenance of an M2-like macrophage phenotype in the tumor microenvironment.Genetic ablation of PHGDH in macrophages from tumor-bearing mice results in attenuated tumor growth,reduced TAM infiltration,a phenotypic shift of M2-like TAMs toward an M1-like phenotype,downregulated PD-L1 expression and enhanced antitumor T-cell immunity.Our study provides a strong basis for further exploration of PHGDH as a potential target to counteract TAM-mediated immunosuppression and hinder tumor progression.
基金the National Natural Science Foundation of China(NSFC,No.82003186,82073691 and 82373134)the International Science and Technology Cooperation Project of China(No.2022YFE0133300)+3 种基金Ningbo Science and Technology Bureau under CM2025 Programme(2020Z092,China)Shenzhen Science and Technology Foundation(JCYJ20210324122006017,China)Tianjin Natural Science Fund(21JCQNJC01910,China)China Postdoctoral Science Foundation e Tianjin Joint Support Program(No.2023T029TJ).
文摘Cancer stem cells(CSCs)play a pivotal role in tumor initiation,proliferation,metastasis,drug resistance,and recurrence.Consequently,targeting CSCs has emerged as a promising avenue for cancer therapy.Recently,3-phosphoglycerate dehydrogenase(PHGDH)has been identified as being intricately associated with the regulation of numerous cancer stem cells.Yet,reports detailing the functional regulators of PHGDH that can mitigate the stemness across cancer types are limited.In this study,the novel“molecular glue”LXH-3-71 was identified,and it robustly induced degradation of PHGDH,thereby modulating the stemness of colorectal cancer cells(CRCs)both in vitro and in vivo.Remarkably,LXH-3-71 was observed to form a dynamic chimera,between PHGDH and the DDB1-CRL E3 ligase.These insights not only elucidate the anti-CSCs mechanism of the lead compound but also suggest that degradation of PHGDH may be a more viable therapeutic strategy than the development of PHGDH inhibitors.Additionally,compound LXH-3-71 was leveraged as a novel ligand for the DDB1-CRL E3 ligase,facilitating the development of new PROTAC molecules targeting EGFR and CDK4 degradation.
基金The authors would like to thank Dawn Merkel’s Bad to the Bone Chili Cook Off,Kellsie’s Hope Foundationthe National Institute of Health(NIH)-National Cancer Institute(NCI)(R01-CA227115)for funding.
文摘At the forefront of cancer research is the rapidly evolving understanding of metabolic reprogramming within cancer cells.The expeditious adaptation to metabolic inhibition allows cells to evolve and acquire resistance to targeted treatments,which makes therapeutic exploitation complex but achievable.3-phosphoglycerate dehydrogenase(PHGDH)is the rate-limiting enzyme of de novo serine biosynthesis and is highly expressed in a variety of cancers,including breast cancer,melanoma,and Ewing’s sarcoma.This review will investigate the role of PHGDH in normal biological processes,leading to the role of PHGDH in the progression of cancer.With an understanding of the molecular mechanisms by which PHGDH expression advances cancer growth,we will highlight the known mechanisms of resistance to cancer therapeutics facilitated by PHGDH biology and identify avenues for combatting PHGDH-driven resistance with inhibitors of PHGDH to allow for the development of effective metabolic therapies.
基金This research was supported by grants from the Tianjin Municipal Natural Science Foundation of China(20JCYBJC00220,QY)from the National Natural Science Foundation of China:81672710(QY),81872239(QY),82073051(TW),81874055(TW),and 81902900(LS).
文摘Serine metabolism is reportedly involved in immune cell functions, but whether and how serine metabolism regulates macrophage polarization remain largely unknown. Here, we show that suppressing serine metabolism, either by inhibiting the activity of the key enzyme phosphoglycerate dehydrogenase in the serine biosynthesis pathway or by exogenous serine and glycine restriction, robustly enhances the polarization of interferon-γ-activated macrophages (M(IFN-γ)) but suppresses that of interleukin-4-activated macrophages (M(IL-4)) both in vitro and in vivo. Mechanistically, serine metabolism deficiency increases the expression of IGF1 by reducing the promoter abundance of S-adenosyl methionine-dependent histone H3 lysine 27 trimethylation. IGF1 then activates the p38-dependent JAK–STAT1 axis to promote M(IFN-γ) polarization and suppress STAT6-mediated M(IL-4) activation. This study reveals a new mechanism by which serine metabolism orchestrates macrophage polarization and suggests the manipulation of serine metabolism as a therapeutic strategy for macrophage-mediated immune diseases.
