Cancers, Vol. 10, Pages 455: Renal Cell Carcinoma Is Abrogated by p53 Stabilization through Transglutaminase 2 Inhibition

Cancers, Vol. 10, Pages 455: Renal Cell Carcinoma Is Abrogated by p53 Stabilization through Transglutaminase 2 Inhibition Cancers doi: 10.3390/cancers10110455 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 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. T...
Source: Cancers - Category: Cancer & Oncology Authors: Tags: Article Source Type: research