β2-adrenogenic signaling regulates NNK-induced pancreatic cancer progression via upregulation of HIF-1α.
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.
Department of Hepatobiliary Surgery, First Affiliated Hospital of Xi'an Jiaotong University, Xi'an 710061, China.
Dong
D
Zhang
Department of Hepatobiliary Surgery, First Affiliated Hospital of Xi'an Jiaotong University, Xi'an 710061, China.
Jianjun
J
Lei
Department of Oncology, First Affiliated Hospital of Xi'an Jiaotong University, Xi'an 710061, China.
Jiguang
J
Ma
Department of Hepatobiliary Surgery, First Affiliated Hospital of Xi'an Jiaotong University, Xi'an 710061, China.
Xin
X
Chen
Department of Hepatobiliary Surgery, First Affiliated Hospital of Xi'an Jiaotong University, Xi'an 710061, China.
Liang
L
Sheng
Department of Hepatobiliary Surgery, First Affiliated Hospital of Xi'an Jiaotong University, Xi'an 710061, China.
Zhengdong
Z
Jiang
Department of Hepatobiliary Surgery, First Affiliated Hospital of Xi'an Jiaotong University, Xi'an 710061, China.
Ligang
L
Nan
Department of Hepatobiliary Surgery, First Affiliated Hospital of Xi'an Jiaotong University, Xi'an 710061, China.
Qinhong
Q
Xu
Department of Hepatobiliary Surgery, First Affiliated Hospital of Xi'an Jiaotong University, Xi'an 710061, China.
Wanxing
W
Duan
Department of Hepatobiliary Surgery, First Affiliated Hospital of Xi'an Jiaotong University, Xi'an 710061, China.
Zheng
Z
Wang
Department of General Surgery, First Affiliated Hospital of Xi'an Jiaotong University, Xi'an 710061, China.
Xuqi
X
Li
Department of Hepatobiliary Surgery, First Affiliated Hospital of Xi'an Jiaotong University, Xi'an 710061, China.
Zheng
Z
Wu
Department of Neurosurgery, Baylor Scott and White Health, Temple, TX, 76508, USA.
Erxi
E
Wu
Department of Hepatobiliary Surgery, First Affiliated Hospital of Xi'an Jiaotong University, Xi'an 710061, China.
Qingyong
Q
Ma
Department of General Surgery, First Affiliated Hospital of Xi'an Jiaotong University, Xi'an 710061, China.
Xiongwei
X
Huo
D000368:Aged; D000818:Animals; D002273:Carcinogens / Q000494:pharmacology*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D018450:Disease Progression; D005260:Female; D055785:Gene Knockdown Techniques; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008819:Mice, Nude; D008875:Middle Aged; D009602:Nitrosamines / Q000494:pharmacology*; D010190:Pancreatic Neoplasms / Q000139:chemically induced / Q000209:etiology* / Q000378:metabolism / Q000473:pathology*; D018343:Receptors, Adrenergic, beta-2 / Q000096:biosynthesis / Q000378:metabolism*; D015398:Signal Transduction; D012907:Smoking / Q000378:metabolism; D015533:Transcriptional Activation; D015854:Up-Regulation
D002273:Carcinogens; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D009602:Nitrosamines; D018343:Receptors, Adrenergic, beta-2; C016583:4-(N-methyl-N-nitrosamino)-1-(3-pyridyl)-1-butanone
4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone; HIF-1α; pancreatic cancer; smoking; β2-adrenogenic signaling