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.
Cancers. 2018 Nov 19*** epublish ***
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
Tumor Microenvironment Research Branch, Division of Cancer Biology, National Cancer Center, Goyang, Gyeonggi-do 10408, Korea. ., Tumor Microenvironment Research Branch, Division of Cancer Biology, National Cancer Center, Goyang, Gyeonggi-do 10408, Korea. ., Tumor Microenvironment Research Branch, Division of Cancer Biology, National Cancer Center, Goyang, Gyeonggi-do 10408, Korea. ., Tumor Microenvironment Research Branch, Division of Cancer Biology, National Cancer Center, Goyang, Gyeonggi-do 10408, Korea. ., Omics Core Lab, National Cancer Center, Goyang, Gyeonggi-do 10408, Korea. ., Tumor Microenvironment Research Branch, Division of Cancer Biology, National Cancer Center, Goyang, Gyeonggi-do 10408, Korea. ., Tumor Microenvironment Research Branch, Division of Cancer Biology, National Cancer Center, Goyang, Gyeonggi-do 10408, Korea. ., Tumor Microenvironment Research Branch, Division of Cancer Biology, National Cancer Center, Goyang, Gyeonggi-do 10408, Korea. ., College of Pharmacy, Kangwon National University, Chuncheon, Gangwon-do 24341, Korea. ., Biometric Research Branch, Division of Cancer Epidemiology and Prevention, National Cancer Center, Goyang, Gyeonggi-do 10408, Korea. ., Songdang Institute for Cancer Research, Yonsei University College of Medicine, Seoul 03722, Korea. ., Songdang Institute for Cancer Research, Division of Medical Oncology, Department of Internal Medicine, Yonsei Cancer Center, Yonsei University College of Medicine, Seoul 03722, Korea. ., Tumor Microenvironment Research Branch, Division of Cancer Biology, National Cancer Center, Goyang, Gyeonggi-do 10408, Korea. .