β2-Adrenogenic signaling regulates NNK-induced pancreatic cancer progression via upregulation of HIF-1α

Abstract

// Dong Zhang 1, * , Jianjun Lei 1, * , Jiguang Ma 2 , Xin Chen 1 , Liang Sheng 1 , Zhengdong Jiang 1 , Ligang Nan 1 , Qinhong Xu 1 , Wanxing Duan 1 , Zheng Wang 1 , Xuqi Li 3 , Zheng Wu 1 , Erxi Wu 4 , Qingyong Ma 1 , Xiongwei Huo 3 1 Department of Hepatobiliary Surgery, First Affiliated Hospital of Xi’an Jiaotong University, Xi’an 710061, China 2 Department of Oncology, First Affiliated Hospital of Xi’an Jiaotong University, Xi’an 710061, China 3 Department of General Surgery, First Affiliated Hospital of Xi’an Jiaotong University, Xi’an 710061, China 4 Department of Neurosurgery, Baylor Scott and White Health, Temple, TX, 76508, USA * These authors have contributed equally to this work Correspondence to: Xiongwei Huo, e-mail: doctorhuoxw@163.com Qingyong Ma, e-mail: qyma56@mail.xjtu.edu.cn Keywords: 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone, smoking, β2-adrenogenic signaling, HIF-1α, pancreatic cancer Received: May 04, 2015      Accepted: September 13, 2015      Published: October 16, 2015 ABSTRACT 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 β 2 -adrenogenic receptor (β 2 -AR) expression are negatively correlated with the overall survival of pancreatic cancer patients. Moreover, HIF-1α expression and β 2 -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 β 2 -AR selective antagonist) abrogates NNK-induced pancreatic cancer proliferation and invasion in vitro and inhibits NNK-induced pancreatic cancer growth in vivo . However, using CoCl 2 (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 β 2 -AR signaling regulates NNK-induced pancreatic cancer progression via upregulation of HIF-1α. Taken together, β 2 -AR signaling and HIF-1α may represent promising therapeutic targets for preventing smoking induced pancreatic cancer progression.