PKLR promotes colorectal cancer liver colonization through induction of glutathione synthesis

Nguyen, Alexander T.; Loo, Jia Min; Mital, Rohit; Weinberg, Ethan M.; Man, Fung Ying; Zeng, Zhaoshi; Paty, Philip B.; Saltz, Leonard B.; Janjigian, Yelena Y.; Stanchina, Elisa de; Tavazoie, Sohail F.

doi:10.1172/jci83587

Cited by 66 publications

(46 citation statements)

References 60 publications

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“…The hypoxia signature was found to be upregulated in all of the liver metastatic derivatives individually and in the composite, where it was the most significantly enriched gene signature (normalized enrichment score (NES)=2.12, q-value<0.001; Fig.S3B). Upregulation of hypoxia genes in the liver metastatic derivatives is consistent with previous reports demonstrating that hypoxia exerts selective pressure in the liver metastatic microenvironment (13,15).…”

Section: Candidate Metastasis Promoting Genes Identified Through Transupporting

confidence: 91%

“…Hypoxia poses a metabolic challenge for cancer cell growth as metabolites needed for biosynthesis of macromolecules required for cell proliferation can become limiting (23,24). In vivo selected cancer cells can alter cellular metabolism in order to better respond to the metastatic microenvironment (13,15). To search for such adaptive metastatic metabolic alterations that associate with enhanced PCK1 expression, we performed metabolomic profiling of the four highly/poorly metastatic CRC PDX pairs.…”

Section: Metabolic Profiling Reveals Pck1-dependent Pyrimidine Nucleomentioning

confidence: 99%

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PCK1 and DHODH drive colorectal cancer liver metastatic colonization and nucleotide biosynthesis under hypoxia

Yamaguchi

Weinberg

Nguyen

et al. 2019

Preprint

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Colorectal cancer (CRC) is a major cause of human death. Mortality is primarily due to metastatic organ colonization, with liver being the primary organ affected. We modeled metastatic CRC (mCRC) liver colonization using patient-derived primary and metastatic tumor xenografts (PDX). Such PDX modeling predicted patient survival outcomes. In vivo selection of multiple PDXs for enhanced metastatic capacity upregulated the gluconeogenic enzyme PCK1, which enhanced metastatic hypoxic survival by driving anabolic pyrimidine nucleotide biosynthesis. Consistently, highly metastatic tumors upregulated multiple pyrimidine biosynthesis intermediary metabolites. Therapeutic inhibition of the pyrimidine biosynthetic enzyme DHODH with oral leflunomide substantially impaired CRC liver metastatic colonization and hypoxic survival. Our findings provide a potential mechanistic basis for the epidemiologic association of anti-

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Section: Candidate Metastasis Promoting Genes Identified Through Transupporting

confidence: 91%

Section: Metabolic Profiling Reveals Pck1-dependent Pyrimidine Nucleomentioning

confidence: 99%

PCK1 and DHODH drive colorectal cancer liver metastatic colonization and nucleotide biosynthesis under hypoxia

Yamaguchi

Weinberg

Nguyen

et al. 2019

Preprint

Self Cite

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“…The finding that distant metastasis is limited by oxidative stress is not an artifact of xenotransplantation into immunocompromised mice as similar results were observed in immunocompetent mice with autochthanous melanomas: Treatment with NAC or vitamin E promoted distant metastasis without affecting the growth of subcutaneous tumors (Le Gal et al 2015). Consistent with this, cancer cells depend on NRF2 (Wang et al 2016), thioredoxinlike 2 (Qu et al 2011), superoxide dismutase (Kamarajugadda et al 2013;Glasauer et al 2014), and glutamate cysteine ligase (the rate-limiting step of glutathione synthesis) (Nguyen et al 2016) to survive during metastasis.…”

Section: Ros and Metastasismentioning

confidence: 63%

Cancer, Oxidative Stress, and Metastasis

Gill

Piskounova

Morrison

2016

Cold Spring Harb Symp Quant Biol

231

164

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Reactive oxygen species (ROS) are highly reactive molecules that arise from a number of cellular sources, including oxidative metabolism in mitochondria. At low levels they can be advantageous to cells, activating signaling pathways that promote proliferation or survival. At higher levels, ROS can damage or kill cells by oxidizing proteins, lipids, and nucleic acids. It was hypothesized that antioxidants might benefit high-risk patients by reducing the rate of ROS-induced mutations and delaying cancer initiation. However, dietary supplementation with antioxidants has generally proven ineffective or detrimental in clinical trials. High ROS levels limit cancer cell survival during certain windows of cancer initiation and progression. During these periods, dietary supplementation with antioxidants may promote cancer cell survival and cancer progression. This raises the possibility that rather than treating cancer patients with antioxidants, they should be treated with pro-oxidants that exacerbate oxidative stress or block metabolic adaptations that confer oxidative stress resistance.

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“…Glutamine starvation of transformed cells reduces their glutathione pool (Yuneva et al , ). Human primary acute myeloid leukemia (AML) and metastatic liver cancer are characterized by significant elevation of the enzymes for glutathione biosynthesis, including GCL and GS (Pei et al , ; Nguyen et al , ), suggesting that these tumors might be sensitive to inhibitors of glutathione biosynthesis.…”

Section: Glutamine Utilization Beyond Protein Synthesismentioning

confidence: 99%

Cancer cell metabolism: the essential role of the nonessential amino acid, glutamine

2017

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Biochemistry textbooks and cell culture experiments seem to be telling us two different things about the significance of external glutamine supply for mammalian cell growth and proliferation. Despite the fact that glutamine is a nonessential amino acid that can be synthesized by cells from glucose-derived carbons and amino acid-derived ammonia, most mammalian cells in tissue culture cannot proliferate or even survive in an environment that does not contain millimolar levels of glutamine. Not only are the levels of glutamine in standard tissue culture media at least ten-fold higher than other amino acids, but glutamine is also the most abundant amino acid in the human bloodstream, where it is assiduously maintained at approximately 0.5 mM through a combination of dietary uptake, synthesis, and muscle protein catabolism. The complex metabolic logic of the proliferating cancer cells' appetite for glutamine-which goes far beyond satisfying their protein synthesis requirements-has only recently come into focus. In this review, we examine the diversity of biosynthetic and regulatory uses of glutamine and their role in proliferation, stress resistance, and cellular identity, as well as discuss the mechanisms that cells utilize in order to adapt to glutamine limitation.

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PKLR promotes colorectal cancer liver colonization through induction of glutathione synthesis

Cited by 66 publications

References 60 publications

PCK1 and DHODH drive colorectal cancer liver metastatic colonization and nucleotide biosynthesis under hypoxia

PCK1 and DHODH drive colorectal cancer liver metastatic colonization and nucleotide biosynthesis under hypoxia

Cancer, Oxidative Stress, and Metastasis

Cancer cell metabolism: the essential role of the nonessential amino acid, glutamine

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