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Renal Cell Carcinoma Is Abrogated by p53 Stabilization through Transglutaminase 2 Inhibition

Authors
 Seon-Hyeong Lee  ;  Won-Kyu Lee  ;  Nayeon Kim  ;  Joon Hee Kang  ;  Kyung-Hee Kim  ;  Seul-Gi Kim  ;  Jae-Seon Lee  ;  Soohyun Lee  ;  Jongkook Lee  ;  Jungnam Joo  ;  Woo Sun Kwon  ;  Sun Young Rha  ;  Soo-Youl Kim 
Citation
 CANCERS, Vol.10(11) : E455, 2018 
Journal Title
 CANCERS 
Issue Date
2018
Keywords
apoptosis ; p53 ; renal cell carcinoma ; streptonigrin ; transglutaminase 2
Abstract
In general, expression of transglutaminase 2 (TGase 2) is upregulated in renal cell carcinoma (RCC), resulting in p53 instability. Previous studies show that TGase 2 binds to p53 and transports it to the autophagosome. Knockdown or inhibition of TGase 2 in RCC induces p53-mediated apoptosis. Here, we screened a chemical library for TGase 2 inhibitors and identified streptonigrin as a potential therapeutic compound for RCC. Surface plasmon resonance and mass spectroscopy were used to measure streptonigrin binding to TGase 2. Mass spectrometry analysis revealed that streptonigrin binds to the N-terminus of TGase 2 (amino acids 95⁻116), which is associated with inhibition of TGase 2 activity in vitro and with p53 stabilization in RCC. The anti-cancer effects of streptonigrin on RCC cell lines were demonstrated in cell proliferation and cell death assays. In addition, a single dose of streptonigrin (0.2 mg/kg) showed marked anti-tumor effects in a preclinical RCC model by stabilizing p53. Inhibition of TGase 2 using streptonigrin increased p53 stability, which resulted in p53-mediated apoptosis of RCC. Thus, targeting TGase 2 may be a new therapeutic approach to RCC.
Files in This Item:
T201805420.pdf Download
DOI
10.3390/cancers10110455
Appears in Collections:
1. College of Medicine (의과대학) > Dept. of Internal Medicine (내과학교실) > 1. Journal Papers
Yonsei Authors
Rha, Sun Young(라선영) ORCID logo https://orcid.org/0000-0002-2512-4531
URI
https://ir.ymlib.yonsei.ac.kr/handle/22282913/167253
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