The Janus-like role of proline metabolism in cancer

Burke, Lynsey; Guterman, Inna; Gallego, Raquel Palacios; Britton, Robert G.; Burschowsky, D.; Tufarelli, Cristina; Rufini, Alessandro

doi:10.1038/s41420-020-00341-8

Cited by 75 publications

(65 citation statements)

References 175 publications

(317 reference statements)

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“…In addition, proline dehydrogenase (PRODH)/proline oxidase, which catalyzes the first step of proline degradation, has been extensively linked to the progression of cancer, including pancreatic cancer. 181 PRODH1 expression is elevated in pancreatic cancer cells to sustain cellular survival and proliferation under low-glucose or Gln-limited conditions. 182 Via experiments with genetically engineered mouse models (GEMMs) and primary pancreatic epithelial cells, a recent study demonstrated that induction of the serine–glycine one-carbon pathway plays a vital role in tumorigenesis.…”

Section: Metabolism Dysregulation In Pancreatic Cancermentioning

confidence: 99%

The molecular biology of pancreatic adenocarcinoma: translational challenges and clinical perspectives

Wang

Zheng

Yang

et al. 2021

Sig Transduct Target Ther

152

128

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Pancreatic cancer is an increasingly common cause of cancer mortality with a tight correspondence between disease mortality and incidence. Furthermore, it is usually diagnosed at an advanced stage with a very dismal prognosis. Due to the high heterogeneity, metabolic reprogramming, and dense stromal environment associated with pancreatic cancer, patients benefit little from current conventional therapy. Recent insight into the biology and genetics of pancreatic cancer has supported its molecular classification, thus expanding clinical therapeutic options. In this review, we summarize how the biological features of pancreatic cancer and its metabolic reprogramming as well as the tumor microenvironment regulate its development and progression. We further discuss potential biomarkers for pancreatic cancer diagnosis, prediction, and surveillance based on novel liquid biopsies. We also outline recent advances in defining pancreatic cancer subtypes and subtype-specific therapeutic responses and current preclinical therapeutic models. Finally, we discuss prospects and challenges in the clinical development of pancreatic cancer therapeutics.

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Section: Metabolism Dysregulation In Pancreatic Cancermentioning

confidence: 99%

The molecular biology of pancreatic adenocarcinoma: translational challenges and clinical perspectives

Wang

Zheng

Yang

et al. 2021

Sig Transduct Target Ther

152

128

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“…Another disease that can be characterized by chronic inflammation and often significant hypoxia is cancer (the 'wound that cannot heal' paradigm). Interestingly, overexpression of PYCR1 has been shown in many cancer types and has even been suggested to be directly pro-tumorigenic (Burke et al 2020). ALDH18A1 protein levels and PYCR1 mRNA have also been shown as upregulated in cancer-associated fibroblasts (CAFs), and silencing of these enzymes perturbed collagen formation, in particular collagen type I, α1 (COL1A1)-a crucial extracellular matrix (ECM) component (Kay et al 2020) (Fig.…”

Section: Local Proline Metabolism: Synthesismentioning

confidence: 99%

Proline metabolism and redox; maintaining a balance in health and disease

2021

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Proline is a non-essential amino acid with key roles in protein structure/function and maintenance of cellular redox homeostasis. It is available from dietary sources, generated de novo within cells, and released from protein structures; a noteworthy source being collagen. Its catabolism within cells can generate ATP and reactive oxygen species (ROS). Recent findings suggest that proline biosynthesis and catabolism are essential processes in disease; not only due to the role in new protein synthesis as part of pathogenic processes but also due to the impact of proline metabolism on the wider metabolic network through its significant role in redox homeostasis. This is particularly clear in cancer proliferation and metastatic outgrowth. Nevertheless, the precise identity of the drivers of cellular proline catabolism and biosynthesis, and the overall cost of maintaining appropriate balance is not currently known. In this review, we explore the major drivers of proline availability and consumption at a local and systemic level with a focus on cancer. Unraveling the main factors influencing proline metabolism in normal physiology and disease will shed light on new effective treatment strategies.

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“…Interest in ALDH4A1 stems from the involvement of proline and hydroxyproline metabolism in many aspects of human health and disease. Proline metabolism plays a central role in the altered metabolism of cancer cells, [3][4][5][6][7] and both the PRODH1 and ALDH4A1 genes are regulated by the tumor suppressor p53. 8,9 Inherited mutations in the ALDH4A1 gene cause hyperprolinemia II, a metabolic disorder that can result in neurological problems, including intellectual disability.…”

Section: Introductionmentioning

confidence: 99%

Structural basis for the stereospecific inhibition of the dual proline/hydroxyproline catabolic enzyme ALDH4A1 by trans‐4‐hydroxy‐L‐proline

et al. 2021

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Aldehyde dehydrogenase 4A1 (ALDH4A1) catalyzes the final steps of both proline and hydroxyproline catabolism. It is a dual substrate enzyme that catalyzes the NAD + -dependent oxidations of L-glutamate-γ-semialdehyde to L-glutamate (proline metabolism), and 4-hydroxy-L-glutamate-γ-semialdehyde to 4-erythro-hydroxy-L-glutamate (hydroxyproline metabolism). Here we investigated the inhibition of mouse ALDH4A1 by the six stereoisomers of proline and 4-hydroxyproline using steady-state kinetics and X-ray crystallography. Trans-4-hydroxy-L-proline is the strongest of the inhibitors studied, characterized by a competitive inhibition constant of 0.7 mM, followed by L-proline (1.9 mM). The other compounds are very weak inhibitors (approximately 10 mM or greater). Insight into the selectivity for L-stereoisomers was obtained by solving crystal structures of ALDH4A1 complexed with trans-4-hydroxy-L-proline and trans-4-hydroxy-D-proline. The structures suggest that the 10-fold greater preference for the L-stereoisomer is due to a serine residue that hydrogen bonds to the amine group of trans-4-hydroxy-L-proline. In contrast, the amine group of the D-stereoisomer lacks a direct interaction with the enzyme due to a different orientation of the pyrrolidine ring. These results suggest that hydroxyproline catabolism is subject to substrate inhibition by trans-4-hydroxy-L-proline, analogous to the known inhibition of proline catabolism by L-proline. Also, drugs targeting the first enzyme of hydroxyproline catabolism, by elevating the level of trans-4-hydroxy-L-proline, may inadvertently impair proline catabolism by the inhibition of ALDH4A1.

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The Janus-like role of proline metabolism in cancer

Cited by 75 publications

References 175 publications

The molecular biology of pancreatic adenocarcinoma: translational challenges and clinical perspectives

The molecular biology of pancreatic adenocarcinoma: translational challenges and clinical perspectives

Proline metabolism and redox; maintaining a balance in health and disease

Structural basis for the stereospecific inhibition of the dual proline/hydroxyproline catabolic enzyme ALDH4A1 by trans‐4‐hydroxy‐L‐proline

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