A Precision Strategy to Cure Renal Cell Carcinoma by Targeting Transglutaminase 2

Kim, Soo-Youl; Keillor, Jeffrey W.

doi:10.3390/ijms21072493

Cited by 5 publications

(10 citation statements)

References 79 publications

(149 reference statements)

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“…This implies that RCC specifically relies on TGase 2 for survival. Several pathways may underlie the constitutive upregulation of TGase 2 expression in RCC [8]. TGase 2 acts as a chaperone protein in addition to its role as a cross-linking enzyme [30].…”

Section: Discussionmentioning

confidence: 99%

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Transglutaminase 2-Mediated p53 Depletion Promotes Angiogenesis by Increasing HIF-1α-p300 Binding in Renal Cell Carcinoma

Lee

Kang

et al. 2020

IJMS

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Angiogenesis and the expression of vascular endothelial growth factor (VEGF) are increased in renal cell carcinoma (RCC). Transglutaminase 2 (TGase 2), which promotes angiogenesis in endothelial cells during wound healing, is upregulated in RCC. Tumor angiogenesis involves three domains: cancer cells, the extracellular matrix, and endothelial cells. TGase 2 stabilizes VEGF in the extracellular matrix and promotes VEGFR-2 nuclear translocation in endothelial cells. However, the role of TGase 2 in angiogenesis in the cancer cell domain remains unclear. Hypoxia-inducible factor (HIF)-1-mediated VEGF production underlies the induction of angiogenesis in cancer cells. In this study, we show that p53 downregulated HIF-1 in RCC, and p53 overexpression decreased VEGF production. Increased TGase 2 promoted angiogenesis by inducing p53 degradation, leading to the activation of HIF-1. The interaction of HIF-1 and p53 with the cofactor p300 is required for stable transcriptional activation. We found that TGase 2-mediated p53 depletion increased the availability of p300 for HIF-1-p300 binding. A preclinical xenograft model suggested that TGase 2 inhibition can reverse angiogenesis in RCC.

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Section: Discussionmentioning

confidence: 99%

“…2.3.2.13) between the γ-carboxamide groups of peptide-bound glutamine residues and the γ-amino groups of protein-and peptide-bound lysine residues [7]. TGase 2 plays an important role in the regulation of p53 in RCC (reviewed in [8]).…”

Section: Introductionmentioning

confidence: 99%

Transglutaminase 2-Mediated p53 Depletion Promotes Angiogenesis by Increasing HIF-1α-p300 Binding in Renal Cell Carcinoma

Lee

Kang

et al. 2020

IJMS

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“…By contrast, recent evidence suggests that TGase 2 may be a good therapeutic target for RCC [ 33 ]. In RCC, TGase 2 is negatively regulated by the von Hippel–Lindau tumor suppressor protein (pVHL) and positively regulated by HIF-1α.…”

Section: Discussionmentioning

confidence: 99%

Inhibition of Transglutaminase 2 but Not of MDM2 Has a Significant Therapeutic Effect on Renal Cell Carcinoma

Kang

Lee

et al. 2020

Cells

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More than 50% of human cancers harbor TP53 mutations and increased expression of Mouse double minute 2 homolog (MDM2), which contribute to cancer progression and drug resistance. Renal cell carcinoma (RCC) has an unusually high incidence of wild-type p53, with a mutation rate of less than 4%. MDM2 is master regulator of apoptosis in cancer cells, which is triggered through proteasomal degradation of wild-type p53. Recently, we found that p53 protein levels in RCC are regulated by autophagic degradation. Transglutaminase 2 (TGase 2) was responsible for p53 degradation through this pathway. Knocking down TGase 2 increased p53-mediated apoptosis in RCC. Therefore, we asked whether depleting p53 from RCC cells occurs via MDM2-mediated proteasomal degradation or via TGase 2-mediated autophagic degradation. In vitro gene knockdown experiments revealed that stability of p53 in RCC was inversely related to levels of both MDM2 and TGase 2 protein. Therefore, we examined the therapeutic efficacy of inhibitors of TGase 2 and MDM2 in an in vivo model of RCC. The results showed that inhibiting TGase 2 but not MDM2 had efficient anticancer effects.

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“… 15 , 16 Transglutaminase has been proposed as a target for treatment of mesothelioma, renal cell carcinoma, and gastric cancers. 17 − 19 …”

Section: Introductionmentioning

confidence: 99%

Naturally Occurring Epsilon Gamma Glutamyl Lysine Isopeptide Crosslinks in Human Neuroblastoma SH-SY5Y Cells

Lockridge

Schopfer

2022

ACS Omega

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Zero-length isopeptide crosslinks between the side chains of glutamine and lysine are the product of transglutaminase activity. It is generally accepted that transglutaminase activity is dormant under physiological conditions because the calcium concentration inside cells is too low to activate transglutaminase to an open conformation with access to the catalytic triad. Traditional assays for transglutaminase activity measure incorporation of biotin pentylamine or of radiolabeled putrescine in the presence of added calcium. In this report, we identified naturally occurring isopeptide crosslinked proteins using the following steps: immunopurification of tryptic peptides by binding to anti-isopeptide antibody 81D1C2, separation of immunopurified peptides by liquid chromatography–tandem mass spectrometry, Protein Prospector database searches of mass spectrometry data for isopeptide crosslinked peptides, and manual evaluation of candidate crosslinked peptide pairs. The most labor intense step was manual evaluation. We developed criteria for accepting and rejecting candidate crosslinked peptides and showed examples of MS/MS spectra that confirm or invalidate a possible crosslink. The SH-SY5Y cells that we examined for crosslinked proteins had not been exposed to calcium and had been lysed in the presence of ethylenediaminetetraacetic acid. This precaution allows us to claim that the crosslinks we found inside the cells occurred naturally under physiological conditions. The quantity of crosslinks was very low, and the crosslinked proteins were mostly low abundance proteins. In conclusion, intracellular transglutaminase crosslinking/transamidase activity is very low but detectable. The low level of intracellular crosslinked proteins is consistent with tight regulation of transglutaminase activity.

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A Precision Strategy to Cure Renal Cell Carcinoma by Targeting Transglutaminase 2

Cited by 5 publications

References 79 publications

Transglutaminase 2-Mediated p53 Depletion Promotes Angiogenesis by Increasing HIF-1α-p300 Binding in Renal Cell Carcinoma

Transglutaminase 2-Mediated p53 Depletion Promotes Angiogenesis by Increasing HIF-1α-p300 Binding in Renal Cell Carcinoma

Inhibition of Transglutaminase 2 but Not of MDM2 Has a Significant Therapeutic Effect on Renal Cell Carcinoma

Naturally Occurring Epsilon Gamma Glutamyl Lysine Isopeptide Crosslinks in Human Neuroblastoma SH-SY5Y Cells

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