Genome-wide CRISPR/Cas9 library screening identified PHGDH as a critical driver for Sorafenib resistance in HCC

Nature Communications, Journal Year: 2019, Volume and Issue: 10(1)

Published: Oct. 15, 2019

Abstract Sorafenib is the standard treatment for advanced hepatocellular carcinoma (HCC). However, development of drug resistance common. By using genome-wide CRISPR/Cas9 library screening, we identify phosphoglycerate dehydrogenase (PHGDH), first committed enzyme in serine synthesis pathway (SSP), as a critical driver resistance. activates SSP by inducing PHGDH expression. With RNAi knockdown and knockout models, show that inactivation paralyzes reduce production αKG, serine, NADPH. Concomitantly, elevates ROS level induces HCC apoptosis upon treatment. More strikingly, inhibitor NCT-503 works synergistically with to abolish growth vivo. Similar findings are also obtained other FDA-approved tyrosine kinase inhibitors (TKIs), including Regorafenib or Lenvatinib. In summary, our results demonstrate targeting an effective approach overcome TKI HCC.

Language: Английский

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Metabolic reprogramming for cancer cells and their microenvironment: Beyond the Warburg Effect

Biochimica et Biophysica Acta (BBA) - Reviews on Cancer, Journal Year: 2018, Volume and Issue: 1870(1), P. 51 - 66

Published: June 28, 2018

Language: Английский

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Hypoxia‐inducible factors: coupling glucose metabolism and redox regulation with induction of the breast cancer stem cell phenotype

The EMBO Journal, Journal Year: 2016, Volume and Issue: 36(3), P. 252 - 259

Published: Dec. 22, 2016

Language: Английский

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Metabolism of Amino Acids in Cancer

Frontiers in Cell and Developmental Biology, Journal Year: 2021, Volume and Issue: 8

Published: Jan. 12, 2021

Metabolic reprogramming has been widely recognized as a hallmark of malignancy. The uptake and metabolism amino acids are aberrantly upregulated in many cancers that display addiction to particular acids. Amino facilitate the survival proliferation cancer cells under genotoxic, oxidative, nutritional stress. Thus, targeting acid is becoming potential therapeutic strategy for patients. In this review, we will systematically summarize recent progress malignancy discuss their interconnection with mammalian target rapamycin complex 1 (mTORC1) signaling, epigenetic modification, tumor growth immunity, ferroptosis. Finally, highlight applications.

Language: Английский

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Targeting amino acid metabolism for cancer therapy

Drug Discovery Today, Journal Year: 2016, Volume and Issue: 22(5), P. 796 - 804

Published: Dec. 14, 2016

Language: Английский

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Tumor suppressor p53 and metabolism

Journal of Molecular Cell Biology, Journal Year: 2018, Volume and Issue: 11(4), P. 284 - 292

Published: Nov. 29, 2018

p53 plays a key role in tumor suppression. The suppressive function of has long been attributed to its ability induce apoptosis, cell cycle arrest, and senescence cells. However, recent studies suggest that other functions also contribute as suppressor, such metabolic regulation. regulates various pathways maintain the homeostasis cells adapt stress. In addition, have shown gain-of-function (GOF) mutant proteins drive reprogramming cancer cells, contributing progression. Further understanding GOF mutants metabolism will provide new opportunities for therapy.

Language: Английский

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Human SHMT inhibitors reveal defective glycine import as a targetable metabolic vulnerability of diffuse large B-cell lymphoma

Proceedings of the National Academy of Sciences, Journal Year: 2017, Volume and Issue: 114(43), P. 11404 - 11409

Published: Oct. 9, 2017

Significance Enzymes of the folate cycle are among most consistently overexpressed proteins in cancer. Whereas multiple clinical agents inhibit thymidylate synthase, no current drugs target incorporation one-carbon into folates via serine hydroxymethyltransferase (SHMT). Using genetics, we show that cancer cells require SHMT to generate tumors. We then describe small-molecule inhibitors, and they block growth many human cells, with B-cell lymphomas particularly sensitive inhibition. find this sensitivity arises from lymphomas’ inability import amino acid glycine, which is made as a byproduct reaction. Thus, have an intrinsic defect import, causes therapeutically targetable metabolic vulnerability.

Language: Английский

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Serine synthesis pathway inhibition cooperates with dietary serine and glycine limitation for cancer therapy

Nature Communications, Journal Year: 2021, Volume and Issue: 12(1)

Published: Jan. 14, 2021

Abstract Many tumour cells show dependence on exogenous serine and dietary glycine starvation can inhibit the growth of these cancers extend survival in mice. However, numerous mechanisms promote resistance to this therapeutic approach, including enhanced expression de novo synthesis pathway (SSP) enzymes or activation oncogenes that drive synthesis. Here we inhibition PHGDH, first step SSP, cooperates with depletion one-carbon metabolism cancer growth. In vitro, PHGDH combined leads a defect global protein synthesis, which blocks an ATF-4 response more broadly impacts protective stress amino acid depletion. vivo, combination diet inhibitor shows efficacy against tumours are resistant drug alone, evidence reduced availability. ATF4-response seen vitro following complete available is not mice, where treatment lower but do eliminate serine. Our results indicate will augment depleted diet.

Language: Английский

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Limited Environmental Serine and Glycine Confer Brain Metastasis Sensitivity to PHGDH Inhibition

Cancer Discovery, Journal Year: 2020, Volume and Issue: 10(9), P. 1352 - 1373

Published: June 22, 2020

A hallmark of metastasis is the adaptation tumor cells to new environments. Metabolic constraints imposed by serine and glycine-limited brain environment restrict metastatic growth. How metastases overcome these growth-prohibitive conditions poorly understood. Here, we demonstrate that 3-phosphoglycerate dehydrogenase (PHGDH), which catalyzes rate-limiting step glucose-derived synthesis, a major determinant in multiple human cancer types preclinical models. Enhanced synthesis proved important for nucleotide production cell proliferation highly aggressive cells. In vivo, genetic suppression pharmacologic inhibition PHGDH attenuated metastasis, but not extracranial growth, improved overall survival mice. These results reveal extracellular amino acid availability determines pathway dependence, suggest inhibitors may be useful treatment metastasis. SIGNIFICANCE: Using proteomics, metabolomics, models, nutrient-limited potentiates susceptibility inhibition. findings underscore importance studying metabolism physiologically relevant contexts, provide rationale using treat metastasis.This article highlighted This Issue feature, p. 1241.

Language: Английский

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Increased Serine Synthesis Provides an Advantage for Tumors Arising in Tissues Where Serine Levels Are Limiting

Cell Metabolism, Journal Year: 2019, Volume and Issue: 29(6), P. 1410 - 1421.e4

Published: March 21, 2019

Language: Английский

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