HO-1 plays a central role in NNK-mediated lung carcinogenesis

¹ Dept of Surgery
² Dept of clinical Oncology, The Chinese University of Hong Kong, Prince of Wales Hospital, Shatin, N.T., Hong Kong.
³ Lung Cancer Research Institute & Cancer Center, Guangdong Provincial People's Hospital, Guangdong, Guangzhou, China.

^* To whom correspondence should be addressed. E-mail: E-mail:gchen{at}cuhk.edu.hk.

	Abstract

NNK, the tobacco-specific nitrosamine, is a potent lung cancer inducer. However, how NNK induces lung cancer is still largely unknown.

We evaluated HO-1 in 30 lung cancer tumour samples and their matched non-tumour tissues from patients with cigarette-smoking history. We also studied HO-1, p21, Bcl-2 families, MAPK and NF-B expressions in lung cancer cells treated with NNK.

The level of HO-1 and p21 was significantly increased in lung tumour tissues. There was a positive relationship between these two proteins in the tumour. NNK stimulated the lung cell proliferation and elevated the levels of HO-1, p21, c-IAP2 and Bcl-2 but down-regulated Bad. These effects of NNK were blocked by ZnPP-XII, an HO-1 inhibitor. The NNK-mediated expression of HO-1 was governed by NF-B and ERK1/2 since block of either prevented the stimulatory effect of NNK on HO-1 as well as HO-1 downstream molecules such as p21, c-IAP2, Bcl-2 and Bad.

In conclusion, HO-1 plays a central role in NNK-mediated cell proliferation by promoting the expression of p21, c-IAP2 and Bcl-2 but inhibiting the activity of Bad. NF-B and ERK1/2 function at the up-stream of HO-1. Therefore, HO-1 is likely to be a potential target in the treatment of smoking-related lung cancer.

Keywords:  ERK, HO-1, lung cancer, NF-B, NNK