Inhibiting both proline biosynthesis and lipogenesis synergistically suppresses tumor growth

Liu, Miao; Wang, Yuanyuan; Yang, Chuanzhen; Ruan, Yuxia; Bai, Changsen; Chu, Qiaoyun; Cui, Yanfen; Chen, Ceshi; Ying, Guoguang; Li, Binghui

doi:10.1084/jem.20191226

Cited by 43 publications

(50 citation statements)

References 56 publications

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“…showed that under hypoxic conditions, proline synthesis and reductive carboxylation, both of which require NADPH, act as alternative bins for electrons so that electron transfer can occur for cellular proliferation [36]. These studies fit well with our observations, where D492M cells indeed have lower oxygen consumption rate [11] and show higher activity of aforementioned pathways.…”

Section: Alterations In Reductive Carboxylation and Redox Metabolism supporting

confidence: 91%

Altered Glutamine Metabolism Exposes EMT Derived Mesenchymal Cells to PI3K/Akt/mTOR Pathway Inhibition

Karvelsson¹,

Sigurdsson²,

Seip³

et al. 2020

Preprint

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Background: Epithelial-to-mesenchymal transition (EMT) is a fundamental developmental process with strong implications in cancer progression. Understanding the metabolic alterations associated with EMT may open new avenues of treatment and prevention.Methods: We utilize 13C carbon analogs of glucose and glutamine to examine difference in internal flux patterns of metabolites in central carbon and lipid metabolism following EMT in breast epithelial cell lines. Furthermore, an isotopomer spectral analysis, 13C-metabolic flux analysis and weighted correlation network analysis are utilized for investigation of the alterations in metabolic functionality following EMT in breast.Results: There are inherent differences in metabolic profiles before and after EMT. We observed EMT-dependent re-routing of TCA-cycle flux characterized by increased mitochondrial IDH2 -mediated reductive carboxylation of glutamine to lipid biosynthesis with a concomitant lowering of glycolytic rates and glutamine-dependent glutathione (GSH) generation. Our network approach identified specific subtype of cancer drugs that are significantly associated with GSH abundance and we confirmed this in vitro.Conclusions: EMT-linked alterations in GSH synthesis modulate the sensitivity of breast epithelial cells to PI3K/Akt/mTOR inhibitors.

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Section: Alterations In Reductive Carboxylation and Redox Metabolism supporting

confidence: 91%

Altered Glutamine Metabolism Exposes EMT Derived Mesenchymal Cells to PI3K/Akt/mTOR Pathway Inhibition

Karvelsson¹,

Sigurdsson²,

Seip³

et al. 2020

Preprint

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“…Accordingly, PYCR1 KD reduces BC cells proliferation and invasiveness and increases the cytotoxicity of chemotherapeutic drugs, thus suggesting that PYCR1 may be a potential therapeutic target for BC (31). Complementary to these findings, Liu et al developed a tool to calculate electrons energy dissipation during metabolic transformations (29), and found that under hypoxic conditions in which the electron transfer chain (ETC) to oxygen is blocked, proliferating cells rewire their metabolism and use Proline biosynthesis and lipogenesis as alternative electron acceptors. Blocking simultaneously ALDH18A1 and lipogenesis inhibits breast tumor growth in vivo and in vitro (29).…”

Section: Proline Biosynthesis Genes Predict Poor Prognosis In Cancermentioning

confidence: 99%

Proline Metabolism in Tumor Growth and Metastatic Progression

et al. 2020

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Cancer cells show a formidable capacity to survive under stringent conditions, to elude mechanisms of control, such as apoptosis, and to resist therapy. Cancer cells reprogram their metabolism to support uncontrolled proliferation and metastatic progression. Phenotypic and functional heterogeneity are hallmarks of cancer cells, which endow them with aggressiveness, metastatic capacity, and resistance to therapy. This heterogeneity is regulated by a variety of intrinsic and extrinsic stimuli including those from the tumor microenvironment. Increasing evidence points to a key role for the metabolism of non-essential amino acids in this complex scenario. Here we discuss the impact of proline metabolism in cancer development and progression, with particular emphasis on the enzymes involved in proline synthesis and catabolism, which are linked to pathways of energy, redox, and anaplerosis. In particular, we emphasize how proline availability influences collagen synthesis and maturation and the acquisition of cancer cell plasticity and heterogeneity. Specifically, we propose a model whereby proline availability generates a cycle based on collagen synthesis and degradation, which, in turn, influences the epigenetic landscape and tumor heterogeneity. Therapeutic strategies targeting this metabolic-epigenetic axis hold great promise for the treatment of metastatic cancers.

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“…This activity might be essential in tumors, such as gliomas, that experience hypoxia and therefore limited ETC activity. Conditions that compromise mitochondrial ETC force cells to increase flux through the glutamine-proline pathway, in order to dissipate electron buildup through NADH oxidation by P5CS and PYCR enzymes 122,123 . This property of PYCR1 to act as a "mitochondrial vent" has wider implications.…”

Section: Proline Biosynthesis and The Tca Cyclementioning

confidence: 99%

“…However, whether this is functionally meaningful is doubtful, as ectopic expression of both the short and long P5CS isoforms in different cell lines had no overt effect on their proliferation or survival 38 . The role of P5CS is likely to be context-specific, as, in breast cancer, CRISPR/Cas9-mediated knockout of P5CS had no impact on tumor growth, but it sensitized cancer cells to pharmacological inhibition of lipogenesis, indicating that inhibition of proline biosynthesis could synergize with therapies targeting lipid metabolism 122 . Recently, increased expression of OAT has been shown to correlate with NSCLC progression, and OAT activity supports proliferation and metastatic spread of NSCLC cells 126 .…”

Section: Other Proline Enzymesmentioning

confidence: 99%

“…The use of RNA-interference-based approaches to gene depletion has been informative, but mostly limited to cell culture work and potentially affected by the lack of selectivity when targeting conserved isoforms. The engineering of more physiologically relevant models, such as inducible knockout mouse models or CRISPR/Cas9 modified organoids, will be key to clarify the function of the different enzymes and their isoforms in vivo, as elegantly demonstrated by the generation by Liu and colleagues of a CRE-inducible P5CS knockout mouse model for the analysis of breast cancer tumorigenesis 122 . These genetically neat models could unravel the different functions of PYCR isoforms in cancer and finally shed light on the role of the neglected PYCR3 gene in physiology and disease, not to mention its potential contribution to the proline cycle.…”

Section: Concluding Remarks and Future Perspectivesmentioning

confidence: 99%

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The Janus-like role of proline metabolism in cancer

et al. 2020

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The metabolism of the non-essential amino acid L-proline is emerging as a key pathway in the metabolic rewiring that sustains cancer cells proliferation, survival and metastatic spread. Pyrroline-5-carboxylate reductase (PYCR) and proline dehydrogenase (PRODH) enzymes, which catalyze the last step in proline biosynthesis and the first step of its catabolism, respectively, have been extensively associated with the progression of several malignancies, and have been exposed as potential targets for anticancer drug development. As investigations into the links between proline metabolism and cancer accumulate, the complexity, and sometimes contradictory nature of this interaction emerge. It is clear that the role of proline metabolism enzymes in cancer depends on tumor type, with different cancers and cancer-related phenotypes displaying different dependencies on these enzymes. Unexpectedly, the outcome of rewiring proline metabolism also differs between conditions of nutrient and oxygen limitation. Here, we provide a comprehensive review of proline metabolism in cancer; we collate the experimental evidence that links proline metabolism with the different aspects of cancer progression and critically discuss the potential mechanisms involved.

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Inhibiting both proline biosynthesis and lipogenesis synergistically suppresses tumor growth

Cited by 43 publications

References 56 publications

Altered Glutamine Metabolism Exposes EMT Derived Mesenchymal Cells to PI3K/Akt/mTOR Pathway Inhibition

Altered Glutamine Metabolism Exposes EMT Derived Mesenchymal Cells to PI3K/Akt/mTOR Pathway Inhibition

Proline Metabolism in Tumor Growth and Metastatic Progression

The Janus-like role of proline metabolism in cancer

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