4-(Methylnitrosamino)-1-(3-pyridyl)-1-butanone provokes progression from chronic pancreatitis to pancreatic intraepithelial neoplasia

Xin Chen; Liang Sheng; Jiguang Ma; Dan Qi; Xuqi Li; Zheng Wang; Zheng Wu; Lucas Wong; Jason H Huang; Erxi Wu; Qingyong Ma; Dong Zhang

doi:10.1016/j.isci.2021.103647

4-(Methylnitrosamino)-1-(3-pyridyl)-1-butanone provokes progression from chronic pancreatitis to pancreatic intraepithelial neoplasia

iScience. 2021 Dec 18;25(1):103647. doi: 10.1016/j.isci.2021.103647. eCollection 2022 Jan 21.

Authors

Xin Chen^{1

2}, Liang Sheng¹, Jiguang Ma³, Dan Qi^{4

5}, Xuqi Li⁶, Zheng Wang¹, Zheng Wu¹, Lucas Wong⁷, Jason H Huang^{4

5

8}, Erxi Wu^{4

5

8

9

10}, Qingyong Ma¹, Dong Zhang¹

Affiliations

¹ Department of Hepatobiliary Surgery, First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China.
² Department of Otorhinolaryngology-Head and Neck Surgery, First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China.
³ Department of Anesthesiology, First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China.
⁴ Department of Neurosurgery, Baylor Scott and White Health, Temple, TX, USA.
⁵ Neuroscience Institute, Baylor Scott and White Health, Temple, TX, USA.
⁶ Department of General Surgery, First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China.
⁷ Division of Hematology/Oncology, Baylor Scott and White Health, Temple, TX, USA.
⁸ Department of Surgery, Texas A and M University College of Medicine, Temple, TX, USA.
⁹ Livestrong Cancer Institutes and Department of Oncology, Dell Medical School, The University of Texas at Austin, Austin, TX 78712, USA.
¹⁰ Department of Pharmaceutical Sciences, Texas A and M University College of Pharmacy, College Station, TX, USA.

Abstract

The risk of pancreatic cancer is higher among people who are cigarette smokers than among non-smokers; however, the action mechanisms of cigarette metabolites are not yet fully understood. In this study, we investigated the effect of 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) in cigarette smoking on chronic pancreatitis and pancreatic cancer as well as the biological mechanism of NNK causing malignant transformation. We show that smoking may promote Kras mutation and P16 promoter methylation from clinical samples and NNK markedly facilitates the growth and migration of pancreatic cancer cells via the activation of Sonic Hedgehog signaling. We demonstrate that NNK promotes acinar-to-ductal metastasis and pancreatic intraepithelial neoplasia in rats with chronic pancreatitis, accompanied by desmoplastic reaction and Gli1 overexpression. Together, we here present evidence that NNK provokes the progression of chronic pancreatitis toward pancreatic cancer and highlight potential strategies and targets for early prevention of pancreatic cancer and its therapeutics.

Keywords: Cancer; Cell biology; Health sciences.