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Open AccessArticle

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

1
Tumor Microenvironment Research Branch, Division of Cancer Biology, National Cancer Center, Goyang, Gyeonggi-do 10408, Korea
2
New Drug Development Center, Osong Medical Innovation Foundation, Cheongju, Chungbuk 28160, Korea
3
Department of Chemistry, College of Science, Dongguk University, 30 Pildong-ro 2-gil, Jung-gu, Seoul 04620, Korea
4
Omics Core Lab, National Cancer Center, Goyang, Gyeonggi-do 10408, Korea
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College of Pharmacy, Kangwon National University, Chuncheon, Gangwon-do 24341, Korea
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Biometric Research Branch, Division of Cancer Epidemiology and Prevention, National Cancer Center, Goyang, Gyeonggi-do 10408, Korea
7
Songdang Institute for Cancer Research, Yonsei University College of Medicine, Seoul 03722, Korea
8
Songdang Institute for Cancer Research, Division of Medical Oncology, Department of Internal Medicine, Yonsei Cancer Center, Yonsei University College of Medicine, Seoul 03722, Korea
*
Author to whom correspondence should be addressed.
Cancers 2018, 10(11), 455; https://doi.org/10.3390/cancers10110455
Received: 12 October 2018 / Revised: 8 November 2018 / Accepted: 14 November 2018 / Published: 19 November 2018
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. View Full-Text
Keywords: streptonigrin; renal cell carcinoma; p53; apoptosis; transglutaminase 2 streptonigrin; renal cell carcinoma; p53; apoptosis; transglutaminase 2
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Lee, S.-H.; Lee, W.-K.; Kim, N.; Kang, J.H.; Kim, K.-H.; Kim, S.-G.; Lee, J.-S.; Lee, S.; Lee, J.; Joo, J.; Kwon, W.S.; Rha, S.Y.; Kim, S.-Y. Renal Cell Carcinoma Is Abrogated by p53 Stabilization through Transglutaminase 2 Inhibition. Cancers 2018, 10, 455.

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