Inhibition of Transglutaminase 2 but Not of MDM2 Has a Significant Therapeutic Effect on Renal Cell Carcinoma

Abstract

More than 50% of human cancers harbor TP53 mutations and increased expression of Mouse double minute 2 homolog (MDM2), which contribute to cancer progression and drug resistance. Renal cell carcinoma (RCC) has an unusually high incidence of wild-type p53, with a mutation rate of less than 4%. MDM2 is master regulator of apoptosis in cancer cells, which is triggered through proteasomal degradation of wild-type p53. Recently, we found that p53 protein levels in RCC are regulated by autophagic degradation. Transglutaminase 2 (TGase 2) was responsible for p53 degradation through this pathway. Knocking down TGase 2 increased p53-mediated apoptosis in RCC. Therefore, we asked whether depleting p53 from RCC cells occurs via MDM2-mediated proteasomal degradation or via TGase 2-mediated autophagic degradation. In vitro gene knockdown experiments revealed that stability of p53 in RCC was inversely related to levels of both MDM2 and TGase 2 protein. Therefore, we examined the therapeutic efficacy of inhibitors of TGase 2 and MDM2 in an in vivo model of RCC. The results showed that inhibiting TGase 2 but not MDM2 had efficient anticancer effects.

Phosphorylation of OCT4 Serine 236 Inhibits Germ Cell Tumor Growth by Inducing Differentiation

“…Animal experiments were performed as described previously [ 49 ]. Briefly, BALB/c-nu mice (female, 6–8 weeks old; Orient Bio, Seongnam, South Korea) were used to establish a tumor xenograft model.…”

“…The immunohistochemistry of mouse xenografts was done as described previously [ 49 ] at the Laboratory Animal Research Facility (National Cancer Center). For the histological analysis, the sections were stained with hematoxylin and eosin (H&E) according to the manufacturer’s protocol.…”

New Therapeutic Interventions for Kidney Carcinoma: Looking to the Future

“…Recent studies have further demonstrated that p53 sequestration into autophagosomes occurs through its interaction with the enzyme TG2, which connects p53 with the autophagic protein SQSTM1/p62 [ 38 ]. Moreover, autophagy-related drug resistance appears to be mediated by TG2; therefore, the inhibition of this enzyme might prevent drug resistance, improving cancer therapy [ 66 ]. Consistently, it was reported that treatment with streptonigrin, a TG2 inhibitor, was able to reduce cancer cell growth in a xenograft model of RCC, confirming that the targeting of TG2 exerts anticancer properties [ 66 ].…”

“…Moreover, autophagy-related drug resistance appears to be mediated by TG2; therefore, the inhibition of this enzyme might prevent drug resistance, improving cancer therapy [ 66 ]. Consistently, it was reported that treatment with streptonigrin, a TG2 inhibitor, was able to reduce cancer cell growth in a xenograft model of RCC, confirming that the targeting of TG2 exerts anticancer properties [ 66 ].…”

Kidney cancer biomarkers and targets for therapeutics: survivin (BIRC5), XIAP, MCL-1, HIF1α, HIF2α, NRF2, MDM2, MDM4, p53, KRAS and AKT in renal cell carcinoma

“…IHC studies in an advanced type 1 sarcomatoid pRCC showed MDM2 expression and amplification [ 119 ]. A recent report indicated that while p53 stability in RCC was inversely related to the expression level of MDM2 and Transglutaminase 2 (TGase2, a protein involved in autophagic protein degradation), inhibition of TGase2 but not MDM2 in an in vivo RCC model had efficient anticancer effects [ 120 ]. However, MDM2 acting as an oncogenic protein may play additional roles besides controlling wild type p53.…”