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Cancer Biol Ther. 2005 Nov;4(11):1195-202. Epub 2005 Nov 3.

NF-kappaB protects rat ARL-6 hepatocellular carcinoma cells against hydrogen peroxide-induced apoptosis.

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  • 1Storr Liver Unit, Westmead Millennium Institute, University of Sydney at Westmead Hospital, Westmead, NSW214-5, Australia.

Abstract

BACKGROUND/AIMS:

Refractoriness of some tumours to apoptosis has been related to over-expression of NF-kappaB, while NF-kappaB inhibition can promote apoptosis in several cell types. We compared NF-kappaB activation profiles between normal rat hepatocytes and ARL-6 rat hepatocellular carcinoma (HCC) cells exposed to hydrogen peroxide (H2O2), and examined whether NF-kappaB activation could explain the observed resistance to apoptosis of ARL-6 cells. We then infected ARL-6 cells with recombinant adenovirus containing mutant (non-degradable) IkBa (Adv-mIkappaBalpha), and examined whether this rendered ARL-6 cells more sensitive to oxidative stress-induced apoptosis.

METHODS:

Cultured primary rat hepatocytes and ARL-6 cells were treated with graded doses of H2O2. To block NF-kappaB, ARL-6 cells were incubated with Adv-mIkappaBalpha for 24 h. Cytotoxicity, NF-kappaB activation, cell proliferation, and apoptosis were determined.

RESULTS:

H2O2 induced more apoptosis in primary hepatocytes than ARL-6 cells, and the relative resistance of ARL-6 cells to H2O2-induced apoptosis was associated with more pronounced NF-kappaB activity. In ARL-6 cells, nuclear translocation of NF-kappaB took place within 2 h of administering H2O2 and remained prominent at 36 h. Adv-mIkappaBalpha sensitized ARL-6 cells to H2O2-induced apoptosis, but cell proliferation was minimally suppressed.

CONCLUSIONS:

Compared with normal hepatocytes, ARL-6 cells are refractory to apoptosis after exposure to H2O2, and this is associated with NF-kappaB activation. Conversely, NF-kappaB inhibition sensitises ARL-6 cells to H2O2-induced apoptosis. Sustained NF-kappaB activation in these HCC cells may protect them against apoptosis produced by oxidative stress.

PMID:
16177566
[PubMed - indexed for MEDLINE]
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