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Targeting the Nuclear Factor-B Rescue Pathway Has Promising Future in Human Renal Cell Carcinoma Therapy

¹ Institut National de la Sante et de la Recherche Medicale U727, Section of Renal Pharmacology and Physiopathology, University Louis Pasteur, School of Medicine; and Departments of ² Pathology, ³ Statistics, and ⁴ Urology, Hôpitaux Universitaires de Strasbourg, Strasbourg, France

Requests for reprints: Thierry Massfelder, Institut National de la Sante et de la Recherche Medicale U727, Section of Renal Pharmacology and Physiopathology, University Louis Pasteur, School of Medicine, Strasbourg 67085, France. Phone: 333-90-24-34-56; Fax: 333-90-24-34-59; E-mail: thierry.massfelder{at}medecine.u-strasbg.fr.

Metastatic renal cell carcinoma (RCC) remains refractory to therapies. The nuclear factor-B (NF-B) transcription factor is involved in cell growth, cell motility, and vascularization. We evaluated whether targeting NF-B could be of therapeutic and prognostic values in human RCC. The activation of the NF-B pathway in human RCC cells and tumors was investigated by Western blot. In vitro, the effects of BAY 11-7085 and sulfasalazine, two NF-B 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-B was analyzed by Western blot, confocal microscopy, NF-B small interfering RNA, and NF-B 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-B. NF-B 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-B inhibition blocked tumor cell growth by inducing cell apoptosis. On the TMA, NF-B 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-B independently of VHL expression and that targeting this pathway has great anticancer potential. [Cancer Res 2007;67(24):11668–76]

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