Dynamic effect of bortezomib on nuclear factor-kappaB activity and gene expression in tumor cells.
Nuclear factor-kappaB (NF-kappaB) influences the initiation, progression, and maintenance of diverse cancer types. Despite current therapeutic efforts to block hyperactive NF-kappaB in cancer cells, the in vivo effects of a drug upon this complex pathway are unclear. We monitored NF-kappaB activity and a fast-expressing reporter level simultaneously in head and neck squamous carcinoma cells by quantitative live microscopy. The real-time single cell assay revealed the tumor necrosis factor-alpha-induced oscillation of NF-kappaB was echoed by equally dynamic reporter expression rate. Bortezomib is a proteasome inhibitor whose anticancer action is partly mediated through inhibition of NF-kappaB. When administered to preactivated cells, the drug gave rise to distinct inhibition dynamics, with discrete pulses of reporter induction remaining for hours. These findings suggest that, contrary to a simplistic presumption for a pathway "blockade," the network dynamics and the intracellular pharmacokinetics of the inhibitor must be critically evaluated in developing strategies for optimal intervention of oncogenic pathways.
Sung
Myong-Hee
MH
Laboratory of Receptor Biology and Gene Expression, National Cancer Institute, National Institutes of Health, Room B602, Bldg. 41, 41 Library Dr., Bethesda, MD 20892, USA. sungm@mail.nih.gov
Bagain
Lorena
L
Chen
Zhong
Z
Karpova
Tatiana
T
Yang
Xinping
X
Silvin
Christopher
C
Voss
Ty C
TC
McNally
James G
JG
Van Waes
Carter
C
Hager
Gordon L
GL
D000970:Antineoplastic Agents / Q000494:pharmacology*; D001897:Boronic Acids / Q000494:pharmacology*; D000069286:Bortezomib; D045744:Cell Line, Tumor; D005455:Fluorescent Antibody Technique; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects*; D006801:Humans; D008962:Models, Theoretical; D016328:NF-kappa B / Q000378:metabolism*; D011719:Pyrazines / Q000494:pharmacology*; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology
D000970:Antineoplastic Agents; D001897:Boronic Acids; D016328:NF-kappa B; D011719:Pyrazines; D014409:Tumor Necrosis Factor-alpha; D000069286:Bortezomib