Open Accessβ2-Adrenogenic signaling regulates NNK-induced pancreatic cancer progression via upregulation of HIF-1α
Author(s) -
Dong Zhang,
Jing Liu,
Jiguang Ma,
Xin Chen,
Liang Sheng,
Zhengdong Jiang,
Ligang Nan,
Qinhong Xu,
Wanxing Duan,
Zheng Wang,
Xuqi Li,
Zheng Wu,
Erxi Wu,
Qingyong Ma,
Xiongwei Huo
Publication year - 2015
Publication title -
oncotarget
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.373
H-Index - 127
ISSN - 1949-2553
DOI - 10.18632/oncotarget.5677
Subject(s) - pancreatic cancer , cancer research , downregulation and upregulation , medicine , cancer , gene knockdown , tumor progression , in vivo , metastasis , biology , apoptosis , biochemistry , microbiology and biotechnology , gene
Cigarette smoking is a risk factor for pancreatic cancer. It is suggested that 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK), a tobacco-specific nitrosamine, mediates the carcinogenic action of cigarette smoking by promoting cancer growth. In the present study, we show that smoking, HIF-1α expression and β2-adrenogenic receptor (β2-AR) expression are negatively correlated with the overall survival of pancreatic cancer patients. Moreover, HIF-1α expression and β2-AR expression are positively correlated with smoking status, different histological differentiation and among the tumor node metastasis (TNM) stages in pancreatic cancer patients. NNK increases HIF-1α expression in pancreatic cancer in vitro and in vivo. Furthermore, knockdown of HIF-1α and ICI118, 551 (a β2-AR selective antagonist) abrogates NNK-induced pancreatic cancer proliferation and invasion in vitro and inhibits NNK-induced pancreatic cancer growth in vivo. However, using CoCl2 (a HIF-1α stabilizing agent which decreases HIF-1α degradation under normoxia conditions) reverses ICI118, 551 induced effects under NNK exposure. Thus, our data indicate that β2-AR signaling regulates NNK-induced pancreatic cancer progression via upregulation of HIF-1α. Taken together, β2-AR signaling and HIF-1α may represent promising therapeutic targets for preventing smoking induced pancreatic cancer progression.