Haem oxygenase-1 plays a central role in NNK-mediated lung carcinogenesis.
The tobacco-specific nitrosamine, 4-(N-methyl-N-nitrosoamino)-1-(3-pyridyl)-1-butanone (NNK), is a potent lung cancer inducer. However, how NNK induces lung cancer is still largely unknown. Haem oxygenase (HO)-1 was evaluated in 30 pairs of lung cancer tumour samples and matched nontumour tissues from patients with a history of cigarette smoking. Expression of HO-1, p21(Cip1/Waf1/Cid1) (p21), B-cell lymphoma (Bcl)-2 family members, mitogen-activated protein kinase and nuclear factor (NF)-kappaB was also studied in lung cancer cells treated with NNK. The levels of HO-1 and p21 were significantly increased in lung tumour tissues. There was a positive relationship between these two proteins in the tumour. NNK stimulated lung cell proliferation and elevated the levels of HO-1, p21, inhibitor of apoptosis protein (c-IAP)2 and Bcl-2, but downregulated Bad. These effects of NNK were blocked by zinc protoporphyrin-XII, an HO-1 inhibitor. The NNK-mediated expression of HO-1 was governed by NF-kappaB and extracellular signal-regulated kinase 1/2, since blocking either of these prevented the stimulatory effect of NNK on HO-1, as well as molecules downstream of HO-1, such as p21, c-IAP2, Bcl-2 and Bad. In conclusion, haem oxygenase-1 plays a central role in NNK-mediated cell proliferation by promoting the expression of p21(Cip1/Waf1/Cid1), inhibitor of apoptosis protein 2 and B-cell lymphoma-2 but inhibiting the activity of Bad. Nuclear factor-kappaB and extracellular signal-regulated kinase 1/2 function upstream of haem oxygenase-1. Therefore, haem oxygenase-1 is likely to be a potential target in the treatment of smoking-related lung cancer.
Li
M-Y
MY
Dept of Surgery, The Chinese University of Hong Kong, Prince of Wales Hospital, Shatin, New Territories, Hong Kong.
Yip
J
J
Hsin
M K Y
MK
Mok
T S K
TS
Wu
Y
Y
Underwood
M J
MJ
Chen
G G
GG
D017209:Apoptosis; D000075747:Baculoviral IAP Repeat-Containing 3 Protein; D002273:Carcinogens; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000378:metabolism; D015536:Down-Regulation; D051547:Heme Oxygenase-1 / Q000378:metabolism / Q000502:physiology*; D006801:Humans; D051034:Inhibitor of Apoptosis Proteins / Q000378:metabolism; D008168:Lung / Q000187:drug effects / Q000378:metabolism; D008175:Lung Neoplasms / Q000139:chemically induced*; D020935:MAP Kinase Signaling System; D016328:NF-kappa B / Q000378:metabolism; D009602:Nitrosamines; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D012907:Smoking; D044767:Ubiquitin-Protein Ligases; D051025:bcl-Associated Death Protein / Q000378:metabolism
C493956:CDKN1A protein, human; D002273:Carcinogens; D050759:Cyclin-Dependent Kinase Inhibitor p21; D051034:Inhibitor of Apoptosis Proteins; D016328:NF-kappa B; D009602:Nitrosamines; D019253:Proto-Oncogene Proteins c-bcl-2; D051025:bcl-Associated Death Protein; C016583:4-(N-methyl-N-nitrosamino)-1-(3-pyridyl)-1-butanone; D051547:Heme Oxygenase-1; C494832:BIRC3 protein, human; D000075747:Baculoviral IAP Repeat-Containing 3 Protein; D044767:Ubiquitin-Protein Ligases