Cancer progression is mediated by proline catabolism in non-small cell lung cancer

Liu, Yating; Mao, Chao; Wang, Min; Liu, Na; Ouyang, Lianlian; Liu, Shouping; Tang, Haosheng; Cao, Yang; Liu, Shuang; Wang, Xiang; Xiao, Desheng; Chen, Ceshi; Shi, Ying; Yan, Qin; Tao, Yongguang

doi:10.1038/s41388-019-1151-5

Cited by 59 publications

(57 citation statements)

References 71 publications

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“…Increased expression of PRODH1 occurs in a subset of NSCLC specimens. Consistent with previous findings 67,69 , this increased expression is p53-dependent, which begs the questions whether NSCLC reliance on PRODH1 persists in cancers in which p53 is mutated 88 . Functionally, PRODH activity drives cell proliferation and tumor growth in vivo and promotes cell migration and invasion 88 .…”

Section: The Ambivalent Role Of Prodh In Cancersupporting

confidence: 89%

“…In this instance, PRODH-mediated generation of ROS is blunted upon knockdown of proline biosynthesis enzymes PYCR1, PYCR2, and PYCR3 88 . This suggests that by recycling P5C back to L-proline, PYCR enzymes fuel PRODH activity and, indirectly, act as pro-oxidants 88 . Indirect evidence in support of this possibility is the reported anti-oxidant effect of P5CDH expression triggered in response to p53 activation 127 .…”

Section: Proline and Rosmentioning

confidence: 96%

“…Whether those cytokines play a direct role in promoting carcinogenesis necessitates further investigation. However, their increased expression in lung adenocarcinoma specimens correlates with poor prognosis 88 .…”

Section: The Ambivalent Role Of Prodh In Cancermentioning

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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Section: The Ambivalent Role Of Prodh In Cancersupporting

confidence: 89%

Section: Proline and Rosmentioning

confidence: 96%

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The Janus-like role of proline metabolism in cancer

et al. 2020

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“…A recent review by Phang et al provided an abridged overview of the functionality of proline in cancer cells, as a source for cellular energy production and as an intermediate between the urea cycle and Krebs cycle [ 120 ]. Several studies have identified that overexpression of proline dehydrogenase, the enzyme involved in proline degradation, promotes cancer progression [ 121 , 122 , 123 ]. Future studies could explore the relationship between increased circulating proline concentrations and lung cancer risk.…”

Section: Discussionmentioning

confidence: 99%

Association between Metabolites and the Risk of Lung Cancer: A Systematic Literature Review and Meta-Analysis of Observational Studies

et al. 2020

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Globally, lung cancer is the most prevalent cancer type. However, screening and early detection is challenging. Previous studies have identified metabolites as promising lung cancer biomarkers. This systematic literature review and meta-analysis aimed to identify metabolites associated with lung cancer risk in observational studies. The literature search was performed in PubMed and EMBASE databases, up to 31 December 2019, for observational studies on the association between metabolites and lung cancer risk. Heterogeneity was assessed using the I2 statistic and Cochran’s Q test. Meta-analyses were performed using either a fixed-effects or random-effects model, depending on study heterogeneity. Fifty-three studies with 297 metabolites were included. Most identified metabolites (252 metabolites) were reported in individual studies. Meta-analyses were conducted on 45 metabolites. Five metabolites (cotinine, creatinine riboside, N-acetylneuraminic acid, proline and r-1,t-2,3,c-4-tetrahydroxy-1,2,3,4-tetrahydrophenanthrene) and five metabolite groups (total 3-hydroxycotinine, total cotinine, total nicotine, total 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol (sum of concentrations of the metabolite and its glucuronides), and total nicotine equivalent (sum of total 3-hydroxycotinine, total cotinine and total nicotine)) were associated with higher lung cancer risk, while three others (folate, methionine and tryptophan) were associated with lower lung cancer risk. Significant heterogeneity was detected across most studies. These significant metabolites should be further evaluated as potential biomarkers for lung cancer.

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“…HIF-1α not only inhibits pyruvate metabolic pathway in mitochondria during glycolysis, but also inhibits fatty acid oxidation (FAO) to promote tumor progression (Fig. 4 ) [ 209 – 211 ]. Mechanistically, two FAO enzymes, medium-chain acyl-CoA dehydrogenase (MCAD) and long-chain acyl-CoA dehydrogenase (LCAD), reduce ROS levels to promote tumor cell proliferation, and loss-of-function of LCAD further accelerates cancer progression via involving in phosphatase and tensin homolog (PTEN) pathway [ 209 ].…”

Section: Role Of Hif-α In Nutrient Deprivation During Cancer Progressmentioning

confidence: 99%

Epigenetic crosstalk between hypoxia and tumor driven by HIF regulation

Mao

Wang

et al. 2020

J Exp Clin Cancer Res

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Hypoxia is the major influence factor in physiological and pathological courses which are mainly mediated by hypoxia-inducible factors (HIFs) in response to low oxygen tensions within solid tumors. Under normoxia, HIF signaling pathway is inhibited due to HIF-α subunits degradation. However, in hypoxic conditions, HIF-α is activated and stabilized, and HIF target genes are successively activated, resulting in a series of tumour-specific activities. The activation of HIFs, including HIF-1α, HIF-2α and HIF-3α, subsequently induce downstream target genes which leads to series of responses, the resulting abnormal processes or metabolites in turn affect HIFs stability. Given its functions in tumors progression, HIFs have been regarded as therapeutic targets for improved treatment efficacy. Epigenetics refers to alterations in gene expression that are stable between cell divisions, and sometimes between generations, but do not involve changes in the underlying DNA sequence of the organism. And with the development of research, epigenetic regulation has been found to play an important role in the development of tumors, which providing accumulating basic or clinical evidences for tumor treatments. Here, given how little has been reported about the overall association between hypoxic tumors and epigenetics, we made a more systematic review from epigenetic perspective in hope of helping others better understand hypoxia or HIF pathway, and providing more established and potential therapeutic strategies in tumors to facilitate epigenetic studies of tumors.

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Cancer progression is mediated by proline catabolism in non-small cell lung cancer

Cited by 59 publications

References 71 publications

The Janus-like role of proline metabolism in cancer

The Janus-like role of proline metabolism in cancer

Association between Metabolites and the Risk of Lung Cancer: A Systematic Literature Review and Meta-Analysis of Observational Studies

Epigenetic crosstalk between hypoxia and tumor driven by HIF regulation

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