AIF Downregulation and Its Interaction with STK3 in Renal Cell Carcinoma

Apoptosis-inducing factor (AIF) plays a crucial role in caspase-independent programmed cell death by triggering chromatin condensation and DNA fragmentation. Therefore, it might be involved in cell homeostasis and tumor development. In this study, we report significant AIF downregulation in the majority of renal cell carcinomas (RCC). In a group of RCC specimens, 84% (43 out of 51) had AIF downregulation by immunohistochemistry stain. Additional 10 kidney tumors, including an oxyphilic adenoma, also had significant AIF downregulation by Northern blot analysis. The mechanisms of the AIF downregulation included both AIF deletion and its promoter methylation. Forced expression of AIF in RCC cell lines induced massive apoptosis. Further analysis revealed that AIF interacted with STK3, a known regulator of apoptosis, and enhanced its phosphorylation at Thr180. These results suggest that AIF downregulation is a common event in kidney tumor development. AIF loss may lead to decreased STK3 activity, defective apoptosis and malignant transformation.