Metastatic
renal cell carcinoma (RCC) remains refractory to
therapies. The
nuclear factor-kappaB (
NF-kappaB)
transcription factor is involved in cell growth, cell motility, and vascularization. We evaluated whether targeting
NF-kappaB could be of therapeutic and prognostic values in human RCC. The activation of the
NF-kappaB pathway in human RCC cells and
tumors was investigated by Western blot. In vitro, the effects of
BAY 11-7085 and
sulfasalazine, two
NF-kappaB inhibitors, on
tumor cell growth were investigated by cell counting,
3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide analysis,
terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling, and fluorescence-activated cell sorting. Their specificity toward
NF-kappaB was analyzed by Western blot, confocal microscopy,
NF-kappaB small interfering RNA, and
NF-kappaB transcription assay. In vivo, the effects of
BAY 11-7085 on the growth of human RCC
tumors were investigated in nude mice. A tissue microarray (TMA) containing 241 cases of human RCC with 12 to 22 years of clinical follow-up and corresponding normal tissues was built up to assess prognostic significance of activated
NF-kappaB.
NF-kappaB is constitutively activated in cultured cells expressing or not the von Hippel-Lindau (VHL) tumor suppressor gene as a consequence of Akt
kinase activation and in
tumors. In vitro and in vivo
NF-kappaB inhibition blocked
tumor cell growth by inducing cell apoptosis. On the TMA,
NF-kappaB activation was correlated with
tumor dimension but was not found to be an independent prognostic factor for patient survival. This report provides strong evidence that the mechanisms responsible for the intrinsic resistance of RCC cells to apoptosis converge on
NF-kappaB independently of VHL expression and that targeting this pathway has great anticancer potential.