Potential therapeutic target secretogranin II might cooperate with hypoxia-inducible factor 1 & alpha; in sunitinib-resistant renal cell carcinoma

Multitargeted receptor tyrosine kinase inhibitors, including vascular endothelial growth factor (VEGF) inhibitors, such as sunitinib, have been used as the primary targeted agents for patients with recurrent or distant metastasis of advanced renal cell carcinoma (RCC). However, endogenous or acquired sunitinib resistance has become a significant therapeutic problem. Therefore, we focused on mechanisms of sunitinib resistance in RCC. First, we undertook RNA sequencing analysis using previously established sunitinib-resistant RCC (SUR-Caki1, SUR-ACHN, and SUR-A498) cells. The results showed increased expression of secretogranin II (SCG2, chromogranin C) in SUR-RCC cells compared to parental cells. The Cancer Genome Atlas database showed that SCG2 expression was increased in RCC compared to normal renal cells. In addition, the survival rate of the SCG2 high-expression group was significantly lower than that of the RCC low-expression group. Thus, we investigated the involvement of SCG2 in sunitinib-resistant RCC. In vitro analysis showed that migratory and invasive abilities were suppressed by SCG2 knockdown SUR cells. As SCG2 was previously reported to be associated with angiogenesis, we undertook a tube formation assay. The results showed that suppression of SCG2 inhibited angiogenesis. Furthermore, coimmunoprecipitation assays revealed a direct interaction between SCG2 and hypoxia-inducible factor 1a (HIF1a). Expression levels of VEGF-A and VEGF-C downstream of HIF1a were found to be decreased in SCG2 knockdown SUR cells. In conclusion, SCG2 could be associated with sunitinib resistance through VEGF regulation in RCC cells. These findings could lead to a better understanding of the VHL/HIF/VEGF pathway and the development of new therapeutic strategies for sunitinib-resistant RCC.

Automated summary

Multitargeted receptor tyrosine kinase inhibitors, including VEGF inhibitors like sunitinib, have been commonly used in the treatment of advanced renal cell carcinoma (RCC) with recurrent or distant metastasis. However, the development of sunitinib resistance has become a major challenge. In this study, RNA sequencing analysis revealed that increased expression of secretogranin II (SCG2) was associated with sunitinib-resistant RCC cells. Further investigations showed that SCG2 knockdown inhibited migratory and invasive abilities of RCC cells, suppressed angiogenesis, and decreased VEGF expression. These findings suggest that SCG2 may play a role in sunitinib resistance through VEGF regulation in RCC cells, providing potential targets for the development of novel therapeutic strategies.