Renal cell carcinoma is abrogated by p53 stabilization through transglutaminase 2 inhibition

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

Research output: Contribution to journalArticle

1 Citation (Scopus)

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.

Original languageEnglish
Article number455
JournalCancers
Volume10
Issue number11
DOIs
Publication statusPublished - 2018 Nov 19

    Fingerprint

All Science Journal Classification (ASJC) codes

  • Oncology
  • Cancer Research

Cite this

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. (2018). Renal cell carcinoma is abrogated by p53 stabilization through transglutaminase 2 inhibition. Cancers, 10(11), [455]. https://doi.org/10.3390/cancers10110455