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

• Main 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
• Format: Article
• Language: English
• Published: MDPI AG 2018-11-01
• Series: Cancers
• Subjects: streptonigrin; renal cell carcinoma; p53; apoptosis; transglutaminase 2
• Online Access: https://www.mdpi.com/2072-6694/10/11/455

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.