Nicotine enhances the malignant potential of human pancreatic cancer cells via activation of atypical protein kinase C

Takehiko Hanaki, Yosuke Horikoshi, Kazuhiro Nakaso, Masato Nakasone, Yoshinori Kitagawa, Masataka Amisaki, Yosuke Arai, Naruo Tokuyasu, Teruhisa Sakamoto, Soichiro Honjo, Hiroaki Saito, Masahide Ikeguchi, Kazunari Yamashita, Shigeo Ohno, Tatsuya Matsura

Research output: Contribution to journalArticlepeer-review

18 Citations (Scopus)

Abstract

Background 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. Methods 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. Results 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. Conclusions and general significance Nicotine induces aberrant activation of aPKC via nAChR/PI3K signaling in PC cells, resulting in enhancement of cellular proliferation, migration and invasion.

Original languageEnglish
Pages (from-to)2404-2415
Number of pages12
JournalBiochimica et Biophysica Acta - General Subjects
Volume1860
Issue number11
DOIs
Publication statusPublished - 2016 Nov 1
Externally publishedYes

Keywords

  • Atypical protein kinase C
  • Epithelial-mesenchymal transition
  • Nicotine
  • Nicotine acetylcholine receptor
  • Pancreatic cancer
  • Phosphatidylinositol 3-kinase

ASJC Scopus subject areas

  • Biophysics
  • Biochemistry
  • Molecular Biology

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