Constitutive activation of NF-kappaB causes resistance to apoptosis in human cutaneous T cell lymphoma HuT-78 cells. Autocrine role of tumor necrosis factor and reactive oxygen intermediates.
How tumor cells develop resistance to apoptosis induced by cytokines and chemotherapeutic agents is incompletely understood. In the present report, we investigated apoptosis induction by tumor necrosis factor (TNF) in two human T cell lines, Jurkat and HuT-78. While TNF inhibited the growth of Jurkat cells and activated caspase-3, it had no effect on HuT-78 cells. It was further found that HuT-78 cells constitutively expressed the nuclear transcription factor NF-kappaB. TNF activated NF-kappaB in Jurkat cells but not in HuT-78 cells. HuT-78 cells were also resistant to NF-kappaB activation induced by phorbol ester, H2O2, ceramide, endotoxin, and interleukin-1. Despite the presence of preactivated NF-kappaB, HuT-78 cells also expressed high levels of IkappaB-alpha, the inhibitory subunit of NF-kappaB and, unlike Jurkat cells, were resistant to TNF-induced degradation of IkappaB-alpha. Its half-life in HuT-78 cells was 12 h as opposed to 45 min in Jurkat cells. Antibodies against TNF blocked the constitutive activation of NF-kappaB and proliferation of HuT-78 cells but had no significant effect on Jurkat cells, suggesting an autocrine role for TNF. The antioxidant pyrrolidine dithiocarbamate also suppressed constitutive NF-kappaB activation and it reversed the cell's sensitivity to TNF-induced cytotoxicity and activation of caspase-3. Overall, these results suggest that constitutive activation of NF-kappaB, TNF, and prooxidant pathway in certain T cell lymphomas causes resistance to apoptosis, and this can be reversed by antioxidants.
Giri
D K
DK
Cytokine Research Laboratory, Department of Molecular Oncology, The University of Texas M. D. Anderson Cancer Center, Houston, Texas 77030, USA.
Aggarwal
B B
BB
D017209:Apoptosis; D001483:Base Sequence; D015500:Chloramphenicol O-Acetyltransferase / Q000235:genetics; D017930:Genes, Reporter; D006801:Humans; D016399:Lymphoma, T-Cell / Q000378:metabolism* / Q000473:pathology; D016328:NF-kappa B / Q000378:metabolism*; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D011759:Pyrrolidines / Q000494:pharmacology; D017382:Reactive Oxygen Species; D012878:Skin Neoplasms / Q000378:metabolism* / Q000473:pathology; D013859:Thiocarbamates / Q000494:pharmacology; D051841:Transcription Factor RelB; D014157:Transcription Factors; D014158:Transcription, Genetic; D014407:Tumor Cells, Cultured; D014409:Tumor Necrosis Factor-alpha / Q000502:physiology*
D016328:NF-kappa B; D011518:Proto-Oncogene Proteins; D011759:Pyrrolidines; C497593:RELB protein, human; D017382:Reactive Oxygen Species; D013859:Thiocarbamates; D014157:Transcription Factors; D014409:Tumor Necrosis Factor-alpha; D051841:Transcription Factor RelB; C020972:pyrrolidine dithiocarbamic acid; D015500:Chloramphenicol O-Acetyltransferase