PHGDH as a mechanism for resistance in metabolically-driven cancers

Rathore, Richa; Schutt, Charles R.; Tine, Brian A. Van

doi:10.20517/cdr.2020.46

Cited by 24 publications

(28 citation statements)

References 104 publications

(138 reference statements)

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“…Upregulation of PHGDH has been observed in many cancers, including melanoma, breast cancer, leukemia and colorectal cancer ( Locasale et al, 2011 ) ( Fan et al, 2015 ) ( Polet et al, 2016 ) ( Jia et al, 2016 ) ( Zhao et al, 2020 ). This upregulation is thought to be linked to increased demands for folate and methionine cycle-related processes such as DNA synthesis, biomass production and epigenetic modifications ( Rathore et al, 2020 ). Targeting the folate cycle is a mainstay of treatment in several cancers, including OS, with MTX being one of the oldest and still most widely used chemotherapeutics ( Ghodke-Puranik et al, 2015 ).…”

Section: Mitochondria and Metabolic Reprogrammingmentioning

confidence: 99%

Insight into the interplay between mitochondria-regulated cell death and energetic metabolism in osteosarcoma

Lai

Naumova

Marchais

et al. 2022

Front. Cell Dev. Biol.

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Osteosarcoma (OS) is a pediatric malignant bone tumor that predominantly affects adolescent and young adults. It has high risk for relapse and over the last four decades no improvement of prognosis was achieved. It is therefore crucial to identify new drug candidates for OS treatment to combat drug resistance, limit relapse, and stop metastatic spread. Two acquired hallmarks of cancer cells, mitochondria-related regulated cell death (RCD) and metabolism are intimately connected. Both have been shown to be dysregulated in OS, making them attractive targets for novel treatment. Promising OS treatment strategies focus on promoting RCD by targeting key molecular actors in metabolic reprogramming. The exact interplay in OS, however, has not been systematically analyzed. We therefore review these aspects by synthesizing current knowledge in apoptosis, ferroptosis, necroptosis, pyroptosis, and autophagy in OS. Additionally, we outline an overview of mitochondrial function and metabolic profiles in different preclinical OS models. Finally, we discuss the mechanism of action of two novel molecule combinations currently investigated in active clinical trials: metformin and the combination of ADI-PEG20, Docetaxel and Gemcitabine.

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Section: Mitochondria and Metabolic Reprogrammingmentioning

confidence: 99%

Insight into the interplay between mitochondria-regulated cell death and energetic metabolism in osteosarcoma

Lai

Naumova

Marchais

et al. 2022

Front. Cell Dev. Biol.

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“…( 18 ) demonstrated that PHGDH is a major determinant of brain metastasis in multiple human cancer types and preclinical models and explored the possibility of PHGDH inhibitors for treating brain tumor metastasis. These findings suggest that targeting PHGDH provides a promising anticancer and drug resistance approach ( 19 ).…”

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confidence: 99%

Dimerization of PHGDH via the catalytic unit is essential for its enzymatic function

Qing

Wang

et al. 2021

Journal of Biological Chemistry

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Human D-3-phosphoglycerate dehydrogenase (PHGDH), a key enzyme in de novo serine biosynthesis, is amplified in various cancers and serves as a potential target for anticancer drug development. To facilitate this process, more information is needed on the basic biochemistry of this enzyme. For example, PHGDH was found to form tetramers in solution and the structure of its catalytic unit (sPHGDH) was solved as a dimer. However, how the oligomeric states affect PHGDH enzyme activity remains elusive. We studied the dependence of PHGDH enzymatic activity on its oligomeric states. We found that sPHGDH forms a mixture of monomers and dimers in solution with a dimer dissociation constant of ∼0.58 μM, with the enzyme activity depending on the dimer content. We computationally identified hotspot residues at the sPHGDH dimer interface. Single-point mutants at these sites disrupt dimer formation and abolish enzyme activity. Molecular dynamics simulations showed that dimer formation facilitates substrate binding and maintains the correct conformation required for enzyme catalysis. We further showed that the full-length PHGDH exists as a dynamic mixture of monomers, dimers, and tetramers in solution with enzyme concentration-dependent activity. Mutations that can completely disrupt the sPHGDH dimer show different abilities to interrupt the full-length PHGDH tetramer. Among them, E108A and I121A can also disrupt the oligomeric structures of the full-length PHGDH and abolish its enzyme activity. Our study indicates that disrupting the oligomeric structure of PHGDH serves as a novel strategy for PHGDH drug design and the hotspot residues identified can guide the design process.

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“…Multiple efforts have identified targets of the EWS/FLI1 fusion that are involved in ES tumorigenesis, including TRIM8 [20] , H3K27ac , and RNA polymerase II genes [21] . Another approach to combating ESW-FLI1 oncoprotein expression involves targeting L1RAP and phosphoglycerate dehydrogenase (PHGDH), which augment cysteine [22] and serine [23] uptake, or inhibiting BTG [24] , which induces cell proliferation.…”

Section: Oncogenesis Of Sarcomasmentioning

confidence: 99%