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- Title
Renal Cell Carcinoma Is Abrogated by p53 Stabilization through Transglutaminase 2 Inhibition.
- Authors
Lee, Seon-Hyeong; Lee, Won-Kyu; Kim, Nayeon; Kang, Joon Hee; Kim, Kyung-Hee; Kim, Seul-Gi; Lee, Jae-Seon; Lee, Soohyun; Lee, Jongkook; Joo, Jungnam; Kwon, Woo Sun; Rha, Sun Young; Kim, Soo-Youl
- 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.
- Subjects
CELL proliferation; ANTINEOPLASTIC agents; APOPTOSIS; CELL death; CELL lines; MASS spectrometry; NUCLEAR magnetic resonance spectroscopy; RENAL cell carcinoma; TRANSFERASES; TUMOR antigens; PHARMACODYNAMICS
- Publication
Cancers, 2018, Vol 10, Issue 11, p455
- ISSN
2072-6694
- Publication type
Article
- DOI
10.3390/cancers10110455