Tumour necrosis factor-alpha mediates tumour promotion via a PKC alpha- and AP-1-dependent pathway.
Tumour necrosis factor-alpha (TNF-alpha) deficient mice (TNF-alpha(-/-) mice) are resistant to skin carcinogenesis. Cellular signalling via the transcription factor complex AP-1 is thought to play a key role in tumour promotion. The induction of a specific subset of AP-1 responsive genes thought to be important for tumour development, namely GM-CSF, MMP-9 and MMP-3, was suppressed in TNF-alpha(-/-) compared to wild-type mouse skin in response to the tumour promotor TPA. The differential induction of these genes correlated with a temporal shift in AP-1 activation and c-Jun expression in TNF-alpha(-/-) compared to wild-type epidermis. The major receptor for TPA-induced signalling in basal keratinocytes, PKC alpha, was also differentially regulated in wild-type compared with TNF-alpha(-/-) epidermis. A marked delay in TPA-induced intracellular translocation and downregulation of PKC alpha was observed in TNF-alpha(-/-) epidermis, which correlated with the deregulated TPA-induced AP-1 activation and c-Jun expression. The frequency of DNA adduct formation and c-Ha-ras mutations was the same in wild-type and TNF-alpha(-/-) epidermis after DMBA treatment, suggesting that TNF-alpha was not involved in tumour initiation. These data suggest that the pro-inflammatory cytokine TNF-alpha is a critical mediator of tumour promotion, acting via a PKC alpha- and AP-1-dependent pathway. This may be one mechanism by which chronic inflammation increases susceptibility to cancer.
Arnott
Caroline H
CH
Cancer Research UK Translational Oncology Laboratory, Bart's and The London School of Medicine and Dentistry, Queen Mary, University of London, John Vane Science Centre, Charterhouse Square, London EC1M 6BQ, UK.
Scott
Kate A
KA
Moore
Robert J
RJ
Hewer
Alan
A
Phillips
David H
DH
Parker
Peter
P
Balkwill
Frances R
FR
Owens
David M
DM
D015127:9,10-Dimethyl-1,2-benzanthracene / Q000494:pharmacology; D000818:Animals; D002273:Carcinogens / Q000494:pharmacology; D000078404:Epidermal Cells; D004817:Epidermis / Q000187:drug effects / Q000378:metabolism; D007527:Isoenzymes / Q000502:physiology*; D015603:Keratinocytes / Q000187:drug effects; D007700:Kinetics; D020782:Matrix Metalloproteinases / Q000096:biosynthesis / Q000235:genetics; D051379:Mice; D008807:Mice, Inbred BALB C; D018345:Mice, Knockout; D011493:Protein Kinase C / Q000502:physiology*; D051571:Protein Kinase C-alpha; D012333:RNA, Messenger / Q000096:biosynthesis; D015398:Signal Transduction; D012878:Skin Neoplasms / Q000139:chemically induced / Q000378:metabolism*; D013755:Tetradecanoylphorbol Acetate; D018808:Transcription Factor AP-1 / Q000502:physiology*; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics / Q000502:physiology*
D002273:Carcinogens; D007527:Isoenzymes; D012333:RNA, Messenger; D018808:Transcription Factor AP-1; D014409:Tumor Necrosis Factor-alpha; D015127:9,10-Dimethyl-1,2-benzanthracene; C496630:Prkca protein, mouse; D011493:Protein Kinase C; D051571:Protein Kinase C-alpha; D020782:Matrix Metalloproteinases; D013755:Tetradecanoylphorbol Acetate