Expression of DJ-1 in Cancer Cells: Its Correlation with Clinical Significance

Kawate, Takahiko; Tsuchiya, Benio; Iwaya, Keiichi

doi:10.1007/978-981-10-6583-5_4

Cited by 23 publications

(16 citation statements)

References 22 publications

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“…DJ-1 is known to interact with and regulate numerous proteins implicated across various biological systems, including neurodegenerative disorders [46,70,71], diabetes [72], and cancer [73]. Numerous studies have addressed interactions of DJ-1 with various forms of native αSyn, including with monomer, oligomer, and amyloid species [49,52,55,74].…”

Section: Discussionmentioning

confidence: 99%

DJ-1 Acts as a Scavenger of α-Synuclein Oligomers and Restores Monomeric Glycated α-Synuclein

et al. 2021

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Glycation of α-synuclein (αSyn), as occurs with aging, has been linked to the progression of Parkinson’s disease (PD) through the promotion of advanced glycation end-products and the formation of toxic oligomers that cannot be properly cleared from neurons. DJ-1, an antioxidative protein that plays a critical role in PD pathology, has been proposed to repair glycation in proteins, yet a mechanism has not been elucidated. In this study, we integrate solution nuclear magnetic resonance (NMR) spectroscopy and liquid atomic force microscopy (AFM) techniques to characterize glycated N-terminally acetylated-αSyn (glyc-ac-αSyn) and its interaction with DJ-1. Glycation of ac-αSyn by methylglyoxal increases oligomer formation, as visualized by AFM in solution, resulting in decreased dynamics of the monomer amide backbone around the Lys residues, as measured using NMR. Upon addition of DJ-1, this NMR signature of glyc-ac-αSyn monomers reverts to a native ac-αSyn-like character. This phenomenon is reversible upon removal of DJ-1 from the solution. Using relaxation-based NMR, we have identified the binding site on DJ-1 for glycated and native ac-αSyn as the catalytic pocket and established that the oxidation state of the catalytic cysteine is imperative for binding. Based on our results, we propose a novel mechanism by which DJ-1 scavenges glyc-ac-αSyn oligomers without chemical deglycation, suppresses glyc-ac-αSyn monomer–oligomer interactions, and releases free glyc-ac-αSyn monomers in solution. The interference of DJ-1 with ac-αSyn oligomers may promote free ac-αSyn monomer in solution and suppress the propagation of toxic oligomer and fibril species. These results expand the understanding of the role of DJ-1 in PD pathology by acting as a scavenger for aggregated αSyn.

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Section: Discussionmentioning

confidence: 99%

DJ-1 Acts as a Scavenger of α-Synuclein Oligomers and Restores Monomeric Glycated α-Synuclein

et al. 2021

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“…DJ-1 could thus be a therapeutic target to prevent excessive inflammation and neuronal injury after ischemic stroke. In addition, DJ-1 expression has been reported to increase in cancer cells, and this increase is important for cancer pathology [ 24 , 25 ]. Increased expression of DJ-1 within brain cells has also been observed in several neurodegenerative diseases, such as Parkinson disease, amyotrophic lateral sclerosis, Creutzfeldt–Jakob disease, Huntington disease, and Alzheimer disease [ 26 – 30 ].…”

Section: Discussionmentioning

confidence: 99%

Extracellular DJ-1 induces sterile inflammation in the ischemic brain

et al. 2021

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Inflammation is implicated in the onset and progression of various diseases, including cerebral pathologies. Here, we report that DJ-1, which plays a role within cells as an antioxidant protein, functions as a damage-associated molecular pattern (DAMP) and triggers inflammation if released from dead cells into the extracellular space. We first found that recombinant DJ-1 protein induces the production of various inflammatory cytokines in bone marrow–derived macrophages (BMMs) and dendritic cells (BMDCs). We further identified a unique peptide sequence in the αG and αH helices of DJ-1 that activates Toll-like receptor 2 (TLR2) and TLR4. In the ischemic brain, DJ-1 is released into the extracellular space from necrotic neurons within 24 h after stroke onset and makes direct contact with TLR2 and TLR4 in infiltrating myeloid cells. Although DJ-1 deficiency in a murine model of middle cerebral artery occlusion did not attenuate neuronal injury, the inflammatory cytokine expression in infiltrating immune cells was significantly decreased. Next, we found that the administration of an antibody to neutralize extracellular DJ-1 suppressed cerebral post-ischemic inflammation and attenuated ischemic neuronal damage. Our results demonstrate a previously unknown function of DJ-1 as a DAMP and suggest that extracellular DJ-1 could be a therapeutic target to prevent inflammation in tissue injuries and neurodegenerative diseases.

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“…PYCR1 has also been linked to protection from ROS in neuronal cells via direct binding to the protein DJ-1 139 . Beyond its known role in neuronal physiology and Parkinson’s disease, DJ-1 is overexpressed in several cancers and has been linked to worse prognosis 140 – 142 . Although any interaction between PYCR1 and DJ-1 in cancer is yet to be established, these data warrant further investigation into their possible cooperation in promoting tumorigenesis by conferring protection to oxidative stress.…”

Section: Proline and Rosmentioning

confidence: 99%

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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Expression of DJ-1 in Cancer Cells: Its Correlation with Clinical Significance

Cited by 23 publications

References 22 publications

DJ-1 Acts as a Scavenger of α-Synuclein Oligomers and Restores Monomeric Glycated α-Synuclein

DJ-1 Acts as a Scavenger of α-Synuclein Oligomers and Restores Monomeric Glycated α-Synuclein

Extracellular DJ-1 induces sterile inflammation in the ischemic brain

The Janus-like role of proline metabolism in cancer

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