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.
Highlights
Renal cell carcinoma (RCC), the most common malignancy of the adult kidney, is resistant to both radiation and chemotherapy; the prognosis remains poor [1]
TGM2 expression in renal cancer tissues was divided into two groups, which were analyzed against the normal tissue with the highest value (Artery-coronary: ~10,000 reads per kilobase million (RPKM))
The results showed a robust expression of p53 in tumors from streptonigrin-treated mice, whereas p53 positive staining was almost absent from the controls, see Figure 5B
Summary
Renal cell carcinoma (RCC), the most common malignancy of the adult kidney, is resistant to both radiation and chemotherapy; the prognosis remains poor [1]. The median progression-free survival time has doubled due to first-line or second-line therapies that target tumor angiogenesis [2,3], about one-third of all patients with RCC develop metastatic disease [4]. There is an unmet need for anti-cancer therapeutics that are effective against RCC. TGase 2 is responsible for the pathogenesis of inflammatory disorders, neurodegeneration, and cancers. TGase 2 plays important roles in fibroblast function [7], wound healing [8], macrophage phagocytosis [9], in the development of cancers [10,11,12], and neurological disorders such as Huntington’s and Alzheimer’s diseases [13,14,15]. Other biological functions of TGase 2 have been discussed in reviews [16,17]; these include nuclear factor κ-light-chain-enhancer of activated B cells (NF-κB) activation through inhibition of nuclear factor of κ light polypeptide gene enhancer in B-cells inhibitor α (I-κBα) [18], hypoxia-inducible factor
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