title: Nicotine enhances the malignant potential of human pancreatic cancer cells via activation of atypical protein kinase C.
abstract: Pancreatic cancer (PC) is the most lethal malignancy among solid tumors, and the most common risk factor for its development is cigarette smoking. Atypical protein kinase C (aPKC) isozymes function in cell polarity, proliferation, and survival, and have also been implicated in carcinogenesis. However, the involvement of aPKC in PC progression and the effect of nicotine, a major component of cigarette smoke, on the biological activities of aPKC remain to be fully elucidated.
  
  
  
  We investigated the effects of nicotine on the proliferation, migration and invasion of the human PC cell lines Panc1 and BxPC3. We analyzed aPKC localization and activity by immunohistochemistry and in vitro kinase assays, respectively, to assess their involvement in the regulation of PC progression. Moreover, we examined the effect of nicotine on implanted peritoneal tumors of PC cells in mice.
  
  
  
  Nicotine enhanced cell proliferation, migration and invasion in Panc1 and BxPC3 cells. In nicotine-treated PC cells, the aPKC was significantly activated. We also found that nicotine induced phosphatidylinositol 3-kinase (PI3K) signal activation, and a specific inhibitor of the nicotine acetylcholine receptor (nAChR) as well as knockdown of nAChR prevented nicotine-mediated Akt phosphorylation and aPKC activation. In a peritoneal dissemination model of PC, nicotine-treated mice had larger tumors and increased numbers of nodules. Immunohistochemistry showed enhanced expression levels of aPKC and phosphorylated Akt in nodules from nicotine-treated mice.
  
  
  
  Nicotine induces aberrant activation of aPKC via nAChR/PI3K signaling in PC cells, resulting in enhancement of cellular proliferation, migration and invasion.
authors.affiliation: Division of Medical Biochemistry, Department of Pathophysiological and Therapeutic Science, Tottori University Faculty of Medicine, Yonago, Japan; Division of Surgical Oncology, Department of Surgery, Tottori University Faculty of Medicine, Yonago, Japan.
authors.forename: Takehiko
authors.initials: T
authors.lastname: Hanaki
authors.affiliation: Division of Medical Biochemistry, Department of Pathophysiological and Therapeutic Science, Tottori University Faculty of Medicine, Yonago, Japan.
authors.forename: Yosuke
authors.initials: Y
authors.lastname: Horikoshi
authors.affiliation: Division of Medical Biochemistry, Department of Pathophysiological and Therapeutic Science, Tottori University Faculty of Medicine, Yonago, Japan.
authors.forename: Kazuhiro
authors.initials: K
authors.lastname: Nakaso
authors.affiliation: Division of Medical Biochemistry, Department of Pathophysiological and Therapeutic Science, Tottori University Faculty of Medicine, Yonago, Japan; Division of Anesthesiology and Critical Care Medicine, Department of Surgery, Tottori University Faculty of Medicine, Yonago, Japan.
authors.forename: Masato
authors.initials: M
authors.lastname: Nakasone
authors.affiliation: Division of Medical Biochemistry, Department of Pathophysiological and Therapeutic Science, Tottori University Faculty of Medicine, Yonago, Japan; Division of Anesthesiology and Critical Care Medicine, Department of Surgery, Tottori University Faculty of Medicine, Yonago, Japan.
authors.forename: Yoshinori
authors.initials: Y
authors.lastname: Kitagawa
authors.affiliation: Division of Surgical Oncology, Department of Surgery, Tottori University Faculty of Medicine, Yonago, Japan.
authors.forename: Masataka
authors.initials: M
authors.lastname: Amisaki
authors.affiliation: Division of Surgical Oncology, Department of Surgery, Tottori University Faculty of Medicine, Yonago, Japan.
authors.forename: Yosuke
authors.initials: Y
authors.lastname: Arai
authors.affiliation: Division of Surgical Oncology, Department of Surgery, Tottori University Faculty of Medicine, Yonago, Japan.
authors.forename: Naruo
authors.initials: N
authors.lastname: Tokuyasu
authors.affiliation: Division of Surgical Oncology, Department of Surgery, Tottori University Faculty of Medicine, Yonago, Japan.
authors.forename: Teruhisa
authors.initials: T
authors.lastname: Sakamoto
authors.affiliation: Division of Surgical Oncology, Department of Surgery, Tottori University Faculty of Medicine, Yonago, Japan.
authors.forename: Soichiro
authors.initials: S
authors.lastname: Honjo
authors.affiliation: Division of Surgical Oncology, Department of Surgery, Tottori University Faculty of Medicine, Yonago, Japan.
authors.forename: Hiroaki
authors.initials: H
authors.lastname: Saito
authors.affiliation: Division of Surgical Oncology, Department of Surgery, Tottori University Faculty of Medicine, Yonago, Japan.
authors.forename: Masahide
authors.initials: M
authors.lastname: Ikeguchi
authors.affiliation: Department of Molecular Biology, Graduate School of Medical Science, Yokohama City University, Yokohama, Japan.
authors.forename: Kazunari
authors.initials: K
authors.lastname: Yamashita
authors.affiliation: Department of Molecular Biology, Graduate School of Medical Science, Yokohama City University, Yokohama, Japan.
authors.forename: Shigeo
authors.initials: S
authors.lastname: Ohno
authors.affiliation: Division of Medical Biochemistry, Department of Pathophysiological and Therapeutic Science, Tottori University Faculty of Medicine, Yonago, Japan. Electronic address: tmatsura@med.tottori-u.ac.jp.
authors.forename: Tatsuya
authors.initials: T
authors.lastname: Matsura
mesh_terms: D000818:Animals; D002460:Cell Line; D045744:Cell Line, Tumor; D002462:Cell Membrane / Q000187:drug effects / Q000378:metabolism; D002465:Cell Movement / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D006801:Humans; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D009361:Neoplasm Invasiveness; D009538:Nicotine / Q000494:pharmacology* / Q000633:toxicity; D010190:Pancreatic Neoplasms / Q000378:metabolism*; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D011493:Protein Kinase C / Q000378:metabolism*; D015398:Signal Transduction; D012907:Smoking / Q000009:adverse effects
chemical_list: D009538:Nicotine; D019869:Phosphatidylinositol 3-Kinases; C115015:PKC-3 protein; D011493:Protein Kinase C
keywords: Atypical protein kinase C; Epithelial-mesenchymal transition; Nicotine; Nicotine acetylcholine receptor; Pancreatic cancer; Phosphatidylinositol 3-kinase