Targeting the nuclear factor-kappaB rescue pathway has promising future in human renal cell carcinoma therapy.
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.
Sourbier
Carole
C
Institut National de la Sante et de la Recherche Medicale U727, Section of Renal Pharmacology and Physiopathology, University Louis Pasteur, School of Medicine, Strasbourg, France.
Danilin
Sabrina
S
Lindner
Véronique
V
Steger
Jacques
J
Rothhut
Sylvie
S
Meyer
Nicolas
N
Jacqmin
Didier
D
Helwig
Jean-Jacques
JJ
Lang
Hervé
H
Massfelder
Thierry
T
D001706:Biopsy; D002292:Carcinoma, Renal Cell / Q000473:pathology / Q000628:therapy*; D002455:Cell Division / Q000187:drug effects; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D005434:Flow Cytometry; D006801:Humans; D007680:Kidney Neoplasms / Q000473:pathology / Q000628:therapy*; D016328:NF-kappa B / Q000037:antagonists & inhibitors / Q000502:physiology*; D009362:Neoplasm Metastasis; D009570:Nitriles / Q000494:pharmacology; D034741:RNA, Small Interfering / Q000235:genetics; D013450:Sulfones / Q000494:pharmacology; D014162:Transfection
C416282:BAY 11-7085; D016328:NF-kappa B; D009570:Nitriles; D034741:RNA, Small Interfering; D013450:Sulfones