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

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

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Streptonigrin
Renal Cell Carcinoma
Mass Spectrometry
Apoptosis
Small Molecule Libraries
transglutaminase 2
Surface Plasmon Resonance
Neoplasms
Cell Death
Cell Proliferation
Amino Acids
Cell Line
Therapeutics

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., ... 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
Lee, Seon Hyeong ; Lee, Won Kyu ; Kim, Nayeon ; Kang, Joon Hee ; Kim, Kyung Hee ; Kim, Seul Gi ; Lee, Jae Seon ; Lee, Soohyun ; Lee, Jongkook ; Joo, Jungnam ; Kwon, Woo Sun ; Rha, Sun Young ; Kim, Soo Youl. / Renal cell carcinoma is abrogated by p53 stabilization through transglutaminase 2 inhibition. In: Cancers. 2018 ; Vol. 10, No. 11.
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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.",
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Lee, SH, Lee, WK, Kim, N, Kang, JH, Kim, KH, Kim, SG, Lee, JS, Lee, S, Lee, J, Joo, J, Kwon, WS, Rha, SY & Kim, SY 2018, 'Renal cell carcinoma is abrogated by p53 stabilization through transglutaminase 2 inhibition', Cancers, vol. 10, no. 11, 455. https://doi.org/10.3390/cancers10110455

Renal cell carcinoma is abrogated by p53 stabilization through transglutaminase 2 inhibition. / Lee, Seon Hyeong; Lee, Won Kyu; Kim, Nayeon; Kang, Joon Hee; Kim, Kyung Hee; Kim, Seul Gi; Lee, Jae Seon; Lee, Soohyun; Lee, Jongkook; Joo, Jungnam; Kwon, Woo Sun; Rha, Sun Young; Kim, Soo Youl.

In: Cancers, Vol. 10, No. 11, 455, 19.11.2018.

Research output: Contribution to journalArticle

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AU - Lee, Seon Hyeong

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AU - Kim, Kyung Hee

AU - Kim, Seul Gi

AU - Lee, Jae Seon

AU - Lee, Soohyun

AU - Lee, Jongkook

AU - Joo, Jungnam

AU - Kwon, Woo Sun

AU - Rha, Sun Young

AU - Kim, Soo Youl

PY - 2018/11/19

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N2 - 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.

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