Wild-type IDH1 inhibits the tumor growth through degrading HIF-α in renal cell carcinoma

The purpose of our study was to explore the effect and intrinsic mechanism of wild-type IDH1 and its substrate alpha-KG on renal cell carcinoma (RCC). IDH1 was observed lower expression in RCC cell lines. Phenotype experiment was carried out in the wild-type IDH1 and mutant IDH1(R132H) plasmid treated cell line. The results showed that the wild-type IDH1 could significantly inhibit the proliferation, migration and promote the apoptosis of RCC cell lines, which were consistent with the IDH1's substrate alpha-KG. The mutant IDH1(R132H) was found to lose this biological function of IDH1. Moreover, we verified the proliferation inhibition of IDH1 in vivo. In addition, we verified the correlation between IDH1 and hypoxia signal-related proteins in vitro and in vivo, specifically, IDH1 overexpression could significantly reduce the expression of HIF-1 alpha and HIF-2 alpha proteins and its downstream proteins (VEGF, TGF-alpha). Furthermore, we preliminarily verified the possibility of alpha-KG in the RCC's treatment by injecting alpha-KG into the xenograft model. alpha-KG significantly reduced tumor size and weight in tumor-bearing mice. This study provided a new therapeutic target and small molecule for the study of the treatment and mechanism of RCC.

Automated summary

The study found that wild-type IDH1 could inhibit the proliferation and migration of RCC cells, as well as promote apoptosis, while the mutant IDH1 lacked this biological function. Additionally, the study verified the correlation between IDH1 and hypoxia signal-related proteins, and the potential role of α-KG in RCC treatment.