Role of Rel/NF‐κB transcription factors in apoptosis of human hepatocellular carcinoma cells

Abstract

BACKGROUNDPrimary hepatocellular carcinoma (HCC) is one of the 10 most common human carcinomas in the world. The mechanism by which HCC cells resist apoptosis induced by various treatment modalities is poorly understood.METHODSThe authors sought to determine whether Rel/NF‐κB transcription factors play a key role in controlling apoptosis in human HCCcells. We assessed constitutive and inducible activation of NF‐κB in hepatitis B virus (HBV)‐positive (Hep3B) and in hepatitis virus‐negative (Chang, HepG2) HCC cells, as well as the role of known inhibitors of NF‐κB activity.RESULTSThe current study data demonstrate that 1) RelA/NF‐κB activity is activated constitutively in Hep3B cells, as determined by electrophoretic mobility shift assays; 2) RelA/NF‐κB reporter gene activity is inhibited specifically by dominant‐negative mutants of IκBα, IKK1, IKK2, MEKK1, and MEKK3 and it is activated by overexpression of wild‐type MEKK3, suggesting that upstream kinase cascades induce phosphorylation of IκBα and activate RelA/NF‐κB in Hep3B cells; 3) overexpression of the HBV x gene fails to activate NF‐κB in HepG2 and Chang cell lines; 4) The NF‐κB–inducible gene, bcl‐xl, is overexpressed in Hep3B cells and is inhibited by the proteosome inhibitor PS341, which prevents IκBα degradation and RelA/NF‐κB activation; and 5) inhibition of constitutive RelA/NF‐κB activity by PS341 sensitizes Hep3B cells to doxorubicin‐induced apoptosis.CONCLUSIONSThese results are consistent with the role of RelA/NF‐κB activity in the regulation of apoptosis through activation of its downstream target genes and suggest that signaling pathways that control RelA/NF‐κB activity may be important targets for novel therapeutic approaches in the treatment of human HCC. Cancer 2002;95:1696–705. © 2002 American Cancer Society.DOI 10.1002/cncr.10829

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

“…Others have also found that HCC cells constitutively express high levels of NF-κB. 5,46,47 In the present study, ARL-6 cells were more responsive to H 2 O 2 -mediated activation of NF-κB than normal hepatocytes, as shown by translocation of the p65 subunit of NF-κB to the nucleus, and enhanced DNA binding by EMSA assay. In other work (Qiao et al, unpublished data) we have found similar results for the human HCC cell line, HuH7.…”

Rho/Rhotekin-mediated NF-κB activation confers resistance to apoptosis

“…In addition, the Ras/MAP kinase pathway, which has been shown to block cell death in other systems, was not involved in RTKN-mediated antiapoptosis. Elevated NF-kB activity has been found in a number of malignant tumors (Arlt et al, 2002;Bhat-Nakshatri et al, 2002;Chiao et al, 2002). Permanent amplification of NF-kB activity may involve mutations and/or over-representation of members of the Rel protein family (Romero and Humphries, 1995), IkBa gene, or IKKs (DiDonato et al, 1997;RomieuMourez et al, 2001;Sanlioglu et al, 2001).…”

Endoplasmic Reticulum Stress Stimulates the Expression of Cyclooxygenase-2 through Activation of NF-κB and pp38 Mitogen-activated Protein Kinase

“…Furthermore, NF-B plays an important role in liver carcinogenesis (64,65). Activation of NF-B was observed frequently in hepatocarcinoma, and the essential role of NF-B for cancer growth was confirmed in several human cancer cell lines (66,67). Therefore, control of NF-B activity may be an important therapeutic target for the treatment of human hepatocarcinoma (68).…”