Nuclear factor-kappa B is upregulated in colorectal cancer

Citation
Ds. Lind et al., Nuclear factor-kappa B is upregulated in colorectal cancer, SURGERY, 130(2), 2001, pp. 363-369
Citations number
30
Categorie Soggetti
Surgery,"Medical Research Diagnosis & Treatment
Journal title
SURGERY
ISSN journal
00396060 → ACNP
Volume
130
Issue
2
Year of publication
2001
Pages
363 - 369
Database
ISI
SICI code
0039-6060(200108)130:2<363:NFBIUI>2.0.ZU;2-S
Abstract
Background. Chemoresistance may involve the anti-apoptotic transcriptional regulator, nuclear factor-kappaB (NF-kappaB). The purpose of this study was to determine whether chemotherapy induces NF-kappaB activation in a human colon cancer cell line (SW48) and whether NF-kappaB is constitutively activ ated in colorectal cancer. Methods. SW48 cells were incubated with gemcitabine hydrochloride (Gemzar) in the presence and absence of the 26s proteasome inhibitor, MG132, and NF- kappaB binding (electrophoretic mobility shift assay), DNA synthesis (triti ated thymidine uptake), cell viability (3-[4,5-dimetltylthiazol-2-yl]-diphe nyltetrazolium bromide assay), and apoptosis (caspase-3 activity) were meas ured at 24 hours. NF-kappaB binding (electrophoretic mobility shift assay) was also assayed in 10 colorectal cancer tumors. Results. SW48 cells demonstrated constitutive NF-kappaB binding that was en hanced by gemcitabine hydrochloride in a dose-dependent manner MG132. inhib ited NF-kappaB binding and enhanced gemcitabine hydrochloride inhibition of DNA synthesis (gemcitabine hydrochloride = 73% +/- 1.4% vs gemcitabine hyd rochloride + MG132 = 6% +/- 0.4%, P < .05), cell killing (gemcitabine hydro chloride = 87% +/- 2.0 vs gemcitabine hydrochloride + MG132 = 25% +/- 1.3%, P < .05), and caspase-3 activity (gemcitabine hydrochloride = 870 +/- 17.4 vs gemcitabine hydrochloride + MG132 = 1075 +/- 20.4, P < .05). NF-<kappa> B binding was increased in 8 of 10 colorectal cancer tumors compared with a djacent normal mucosa. Conclusions. Gemcitabine hydrochloride enhances NF-kappaB binding in a colo rectal cancer cell line, whereas inhibition of NF-kappaB enhances gemcitabi ne hydrochloride's antitumor activity. NF-kappaB is also activated in human colorectal cancer. NF-kappaB may identify chemoresistant tumors, whereas i nhibition of NF-kappaB may be a novel, biologically based therapy.