Transglutaminase 2 inhibitor abrogates renal cell carcinoma in xenograft models

Ku, Bo Mi; Kim, Se-Jin; Kim, Nayeon; Hong, Dongwan; Choi, Yong-Bock; Lee, Seon-Hyeong; Gong, Young‐Dae; Kim, Soo-Youl

doi:10.1007/s00432-014-1623-5

Cited by 32 publications

(48 citation statements)

References 33 publications

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“…PSMA represents the disease state related to RCC staging and neovascularization due to the hematogenous invasion or spread of renal tumor cells [17, 26]. TGase–2 [14, 27] and PD-L1 [25] were also recently described as ineffective prognostic markers, similar to in this study, and are related to inflammatory reactions and disease progression such as metastatic invasion or therapeutic resistance [14, 27, 28]. (Table 3)…”

Section: Discussionmentioning

confidence: 60%

The prognostic value of BAP1, PBRM1, pS6, PTEN, TGase2, PD-L1, CA9, PSMA, and Ki-67 tissue markers in localized renal cell carcinoma: A retrospective study of tissue microarrays using immunohistochemistry

Kim

Park

et al. 2017

PLoS ONE

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Objective To assess the prognostic roles of BAP1, PBRM1, pS6, PTEN, TGase2, PD-L1, CA9, PSMA, and Ki-67 tissue biomarkers in localized renal cell carcinoma (RCC). Methods Patients who underwent a nephrectomy during 1992–2015 and had a primary specimen of their kidney tumor were included. The nine tissue biomarkers were immunohistochemically stained on tissue microarrays of RCC, and the semi-quantitative H-score, including intensity score, was used to grade the sample. The Cox proportional hazards model was used to evaluate tissue markers significant for overall survival (OS), cancer-specific survival (CSS), and recurrence-free survival (RFS) after adjusting for significant clinicopathological parameters. Results Samples from 351 RCC patients were included. The mean age of the patients was 53.9 years; the rates of pathologic T1-2/≥T3 stage, Fuhrman 1+2/3+4 grade, recurrence, and death were 269/65(80.5/19.5%), 222/107 (67.5/32.5%), 6.6%, and 10.5%, respectively. Median OS, CSS, and RFS were 220.6, 220.6, and 147.1 months, respectively. The multivariable analysis showed that pathologic T stage and Fuhrman nuclear grade were significantly associated with OS and CSS. Pathologic T stage and tumor size were associated with RFS. After adjusting for these significant prognostic clinicopathological factors, Ki-67 was significantly associated with OS (hazard ratio [HR], 2.7), CSS (HR, 3.82), and RFS (HR, 4.85) and pS6 was associated with CSS (HR, 8.63) and RFS (HR, 8.51) in the multivariable model (p<0.05). Conclusion pS6 and Ki-67 are significant prognostic factors of RCC; however, BAP1, PBRM1, TGase 2, PD-L1, CA9, PTEN loss, and PSMA markers did not show this association.

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Section: Discussionmentioning

confidence: 60%

The prognostic value of BAP1, PBRM1, pS6, PTEN, TGase2, PD-L1, CA9, PSMA, and Ki-67 tissue markers in localized renal cell carcinoma: A retrospective study of tissue microarrays using immunohistochemistry

Kim

Park

et al. 2017

PLoS ONE

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“…In cancer, TGase 2 knock down causes down regulation of cancer progression because the roles of TGase 2 in cancer converge, promoting cancer progression by way of adhesion, proliferation, and EMT (reviewed in [44,83]). TGase 2 knock down or inhibition by single targeting specifically induces an anti-cancer effect in ccRCC through stabilization of p53, because p53 binds directly to TGase 2 and is thus chaperoned to the autophagosome for degradation [19][20][21]23,67,71]. This is only possible in ccRCC because over 90% of p53 in ccRCC is wild type.…”

Section: Discussionmentioning

confidence: 99%

“…It has been shown that TGase 2 knock down induced p53-mediated cell death [19] and that inhibition of TGase 2 by a single treatment of 0.2 mg/kg of streptonigrin showed almost a complete response of therapeutic effect [23] in ccRCC xenograft models. A series of reports showed that in ccRCC cell lines, cell death was induced by TGase 2 knock down using siRNA of TGase 2, while TGase 2 knock down did not lead to any cell death effect in the normal immortalized cell HEK293 [19][20][21]23,67]. This implies that ccRCC specifically employs TGase 2 for survival.…”

Section: Tgase 2 In Ccrccmentioning

confidence: 99%

“…Although this ensemble of data regarding ccRCC may explain why ccRCC shows resistance to therapeutics, it did not identify any specific therapeutic target for ccRCC. Although transglutaminase 2 (TGase 2) expression is reported to be high in ccRCC, and TGase 2 inhibition showed significant potential for a therapeutic approach for ccRCC in a series of past studies [19][20][21][22][23], the CPTAC study did not reveal any significance of TGase 2 in ccRCC [18]. These analytical results did not seem to fit, in the overall effort to find a cure for ccRCC.…”

Section: Introductionmentioning

confidence: 99%

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

Kim

Keillor

2020

IJMS

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In a recent report, no significance of transglutaminase 2 (TGase 2) was noted in the analyses of expression differences between normal and clear cell renal cell carcinoma (ccRCC), although we found that knock down of TGase 2 induced significant p53-mediated cell death in ccRCC. Generally, to find effective therapeutic targets, we need to identify targets that belong specifically to a cancer phenotype that can be differentiated from a normal phenotype. Here, we offer precise reasons why TGase 2 may be the first therapeutic target for ccRCC, according to several lines of evidence. TGase 2 is negatively regulated by von Hippel-Lindau tumor suppressor protein (pVHL) and positively regulated by hypoxia-inducible factor 1-α (HIF-1α) in renal cell carcinoma (RCC). Therefore, most of ccRCC presents high level expression of TGase 2 because over 90% of ccRCC showed VHL inactivity through mutation and methylation. Cell death, angiogenesis and drug resistance were specifically regulated by TGase 2 through p53 depletion in ccRCC because over 90% of ccRCC express wild type p53, which is a cell death inducer as well as a HIF-1α suppressor. Although there have been no detailed studies of the physiological role of TGase 2 in multi-omics analyses of ccRCC, a life-long study of the physiological roles of TGase 2 led to the discovery of the first target as well as the first therapeutic treatment for ccRCC in the clinical field.

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“…2.3.2.13) between the γ-carboxamide groups of peptide-bound glutamine residues, which act as acyl donors, and the γ-amino groups of protein-and peptide-bound lysine residues, which act as acceptors (Folk 1983). Recently, TGase 2 has been identified as a therapeutic target (Kang et al 2016;Ku et al 2013Ku et al , 2014 as well as a significant clinicopathologic marker in human clear cell renal cell carcinoma (RCC) (Park et al 2015). RCC shows highly increased expression of TGase 2 regardless of mutations, while low expression has been detected in the normal kidney epithelial cell.…”

Section: Introductionmentioning

confidence: 99%

Allosteric inhibition site of transglutaminase 2 is unveiled in the N terminus

et al. 2018

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Previously we have demonstrated transglutaminase 2 (TGase 2) inhibition abrogated renal cell carcinoma (RCC) using GK921 (3-(phenylethynyl)-2-(2-(pyridin-2-yl)ethoxy)pyrido[3,2-b]pyrazine), although the mechanism of TGase 2 inhibition remains unsolved. Recently, we found that the increase of TGase 2 expression is required for p53 depletion in RCC by transporting the TGase 2 (1-139 a.a)-p53 complex to the autophagosome, through TGase 2 (472-687 a.a) binding p62. In this study, mass analysis revealed that GK921 bound to the N terminus of TGase 2 (81-116 a.a), which stabilized p53 by blocking TGase 2 binding. This suggests that RCC survival can be stopped by p53-induced cell death through blocking the p53-TGase 2 complex formation using GK921. Although GK921 does not bind to the active site of TGase 2, GK921 binding to the N terminus of TGase 2 also inactivated TGase 2 activity through acceleration of non-covalent self-polymerization of TGase 2 via conformational change. This suggests that TGase 2 has an allosteric binding site (81-116 a.a) which changes the conformation of TGase 2 enough to accelerate inactivation through self-polymer formation.

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Transglutaminase 2 inhibitor abrogates renal cell carcinoma in xenograft models

Abstract: TGase 2 inhibitor GK921 abrogates RCC growth in xenograft tumor models, suggesting the possibility of a new therapeutic approach to RCC.

Cited by 32 publications

References 33 publications

The prognostic value of BAP1, PBRM1, pS6, PTEN, TGase2, PD-L1, CA9, PSMA, and Ki-67 tissue markers in localized renal cell carcinoma: A retrospective study of tissue microarrays using immunohistochemistry

The prognostic value of BAP1, PBRM1, pS6, PTEN, TGase2, PD-L1, CA9, PSMA, and Ki-67 tissue markers in localized renal cell carcinoma: A retrospective study of tissue microarrays using immunohistochemistry

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

Allosteric inhibition site of transglutaminase 2 is unveiled in the N terminus

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