Apoptosis repressor with caspase recruitment domain (
ARC), an endogenous inhibitor of apoptosis, is upregulated in a number of human
cancers, thereby conferring drug resistance and giving a rationale for the inhibition of
ARC to overcome drug resistance. Our hypothesis was that
ARC would be similarly upregulated and targetable for
therapy in
renal cell carcinoma (RCC). Expression of
ARC was assessed in 85 human RCC samples and paired non-neoplastic kidney by qPCR and immunohistochemistry, as well as in four RCC cell lines by qPCR, Western immunoblot and confocal microscopy. Contrary to expectations,
ARC was significantly decreased in the majority of clear cell RCC and in three (ACHN, Caki-1 and 786-0) of the four RCC cell lines compared with the HK-2 non-cancerous human proximal tubular epithelial cell line. Inhibition of
ARC with
shRNA in the RCC cell line (SN12K1) that had shown increased
ARC expression conferred resistance to
Sunitinib, and upregulated
interleukin-6 (IL-6) and
vascular endothelial growth factor (
VEGF). We therefore propose that decreased
ARC, particularly in clear cell RCC, confers resistance to targeted
therapy through restoration of
tyrosine kinase-independent alternate angiogenesis pathways. Although the results are contrary to expectations from other
cancer studies, they were confirmed here with multiple analytical methods. We believe the highly heterogeneous nature of
cancers like RCC predicate that expression patterns of molecules must be interpreted in relation to respective matched non-neoplastic regions. In the current study, this procedure indicated that
ARC is decreased in RCC.