Reactivation of Dihydroorotate Dehydrogenase-Driven Pyrimidine Biosynthesis Restores Tumor Growth of Respiration-Deficient Cancer Cells

Bajzíková, Martina; Kovářová, Jaromíra; Coelho, Ana R; Boukalová, Štěpána; Oh, Sehyun; Rohlenová, Kateřina; Švec, David; Hubáčková, Soňa; Endaya, Berwini; Judasová, Kristýna; Bezawork-Geleta, Ayenachew; Kľučková, Katarína; Châtre, Laurent; Zobalova, Renata; Nováková, Anna; Vanova, Katerina Hadrava; Ezrova, Zuzana; Maghzal, Ghassan J.; Novais, Silvia Magalhaes; Olšinová, Marie; Krobova, Linda; An, Yong; Davidová, Eliška; Nahácka, Zuzana; Sobol, Margarita; Cunha‐Oliveira, Teresa; Sandoval-Acuña, Cristián; Strnad, Hynek; Zhang, Tongchuan; Huynh, Thanh; Serafim, Teresa L.; Hozák, Pavel; Sardão, Vilma A.; Koopman, Werner J.H.; Ricchetti, Miria; Oliveira, Paulo J.; Kolář, František; Kubista, Mikael; Truksa, Jaroslav; Dvořáková-Hortová, Kateřina; Pacák, Karel; Gürlich, R; Stocker, Roland; Zhou, Yaoqi; Berridge, Michael V.; Park, Sunghyouk; Dong, Lan-Feng; Rohlena, Jakub; Neužil, Jiřı́

doi:10.1016/j.cmet.2018.10.014

Cited by 221 publications

(220 citation statements)

References 93 publications

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“…More recent work has implicated DHODH as a regulator of differentiation in certain myeloid leukemias and pancreatic adenocarcinoma (46,47). Furthermore, Bajzikova et al found that de-novo pyrimidine biosynthesis is essential for mouse breast cancer tumorigenesis in a DHODH dependent manner (48). Our work reveals that beyond effects on cell growth in vitro and primary tumor growth, CRC metastatic progression selects for upregulation of pyrimidine biosynthesis.…”

Section: Discussionsupporting

confidence: 51%

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: Discussionsupporting

confidence: 51%

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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“…This constitutes an irrefutable piece of evidence in favor of the idea that mitochondria must be fully functional to support the growth of cancer cells. Intriguingly, it appears that mtDNA is required for pyrimidine biosynthesis dependent on OXPHOS‐linked dihydroorotate dehydrogenase to overcome cell‐cycle arrest, while mitochondrial ATP generation itself is dispensable for tumorigenesis …”

Section: Introductionmentioning

confidence: 99%

“…Intriguingly, it appears that mtDNA is required for pyrimidine biosynthesis dependent on OXPHOS-linked dihydroorotate dehydrogenase to overcome cell-cycle arrest, while mitochondrial ATP generation itself is dispensable for tumorigenesis. 9 Here, we will briefly review current evidence suggesting that pharmacological inhibition of OXPHOS may have anticancer effects.…”

Section: Introductionmentioning

confidence: 99%

Oxidative phosphorylation as a potential therapeutic target for cancer therapy

Sica

Pedro

Stoll

et al. 2019

Intl Journal of Cancer

147

114

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In contrast to prior belief, cancer cells require oxidative phosphorylation (OXPHOS) to strive, and exacerbated OXPHOS dependency frequently characterizes cancer stem cells, as well as primary or acquired resistance against chemotherapy or tyrosine kinase inhibitors. A growing arsenal of therapeutic agents is being designed to suppress the transfer of mitochondria from stromal to malignant cells, to interfere with mitochondrial biogenesis, to directly inhibit respiratory chain complexes, or to disrupt mitochondrial function in other ways. For the experimental treatment of cancers, OXPHOS inhibitors can be advantageously combined with tyrosine kinase inhibitors, as well as with other strategies to inhibit glycolysis, thereby causing a lethal energy crisis. Unfortunately, most of the preclinical data arguing in favor of OXPHOS inhibition have been obtained in xenograft models, in which human cancer cells are implanted in immunodeficient mice. Future studies on OXPHOS inhibitors should elaborate optimal treatment schedules and combination regimens that stimulate—or at least are compatible with—anticancer immune responses for long‐term tumor control.

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“…Mitochondrial trafficking between stroma and cancer cells is relevant in tumour initiation and progression 3,8,9 and dysfunctions in the distribution of mitochondria are connected with neurodegenerative diseases, including Alzheimer's disease, Huntington's disease or amyotrophic lateral sclerosis [10][11][12][13][14][15] .…”

Section: Introductionmentioning

confidence: 99%

Mitochondria-adaptor TRAK1 promotes kinesin-1 driven transport in crowded environments

Henrichs

Grycová

Bařinka

et al. 2020

Preprint

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Intracellular trafficking of organelles, driven by kinesin-1 stepping along microtubules, underpins essential processes including neuronal activity. In absence of other proteins on the microtubule surface, kinesin-1 performs micron-long runs. Under protein crowding conditions, however, kinesin-1 motility is drastically impeded. It is thus unclear how kinesin-1 acts as an efficient transporter in crowded intracellular environments. Here, we demonstrate that TRAK1 (Milton), an adaptor protein essential for mitochondrial trafficking, activates kinesin-1 and increases its robustness of stepping in protein crowding conditions. Interaction with TRAK1 i) facilitated kinesin-1 navigation around obstacles, ii) increased the probability of kinesin-1 passing through cohesive envelopes of tau and iii) increased the run length of kinesin-1 in cell lysate.We explain the enhanced motility by the observed direct interaction of TRAK1 with microtubules, providing an additional anchor for the kinesin-1-TRAK1 complex. We propose adaptor-mediated tethering as a mechanism regulating kinesin-1 motility in various cellular environments.

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Reactivation of Dihydroorotate Dehydrogenase-Driven Pyrimidine Biosynthesis Restores Tumor Growth of Respiration-Deficient Cancer Cells

Abstract: Graphical Abstract Highlights d Tumorigenesis depends on functional OXPHOS d OXPHOS-derived ATP is not required for tumor formation d DHODH-driven pyrimidine biosynthesis requires CoQ redoxcycling d CoQ redox-cycling via OXPHOS drives tumorigenesis through pyrimidine biosynthesis

Cited by 221 publications

References 93 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

Oxidative phosphorylation as a potential therapeutic target for cancer therapy

Mitochondria-adaptor TRAK1 promotes kinesin-1 driven transport in crowded environments

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