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

• Published in: Biochimica et biophysica acta Vol. 1860; no. 11; pp. 2404 - 2415
• Main Authors: Hanaki, Takehiko, Horikoshi, Yosuke, Nakaso, Kazuhiro, Nakasone, Masato, Kitagawa, Yoshinori, Amisaki, Masataka, Arai, Yosuke, Tokuyasu, Naruo, Sakamoto, Teruhisa, Honjo, Soichiro, Saito, Hiroaki, Ikeguchi, Masahide, Yamashita, Kazunari, Ohno, Shigeo, Matsura, Tatsuya
• Format: Journal Article
• Language: English
• Published: Netherlands Elsevier B.V 01-11-2016
• Subjects: Animals; Atypical protein kinase C; Cell Line; Cell Line, Tumor; Cell Membrane - drug effects; Cell Membrane - metabolism; Cell Movement - drug effects; Cell Proliferation - drug effects; Epithelial-mesenchymal transition; Humans; Male; Mice; Mice, Inbred BALB C; Neoplasm Invasiveness; Nicotine; Nicotine - pharmacology; Nicotine - toxicity; Nicotine acetylcholine receptor; Pancreatic cancer; Pancreatic Neoplasms - metabolism; Phosphatidylinositol 3-kinase; Phosphatidylinositol 3-Kinases - metabolism; Protein Kinase C - metabolism; Signal Transduction; Smoking - adverse effects; Atypical protein kinase C; Nicotine acetylcholine receptor; IP; aPKC; MCA; Llgl2; EMT; Ly; Par6; CS; Epithelial-mesenchymal transition; PC; PI3K; ζPS; nAChR; Pancreatic cancer; Phosphatidylinositol 3-kinase; Nicotine
• ISSN: 0304-4165; 0006-3002; 1872-8006
• DOI: 10.1016/j.bbagen.2016.07.008

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.
•Nicotine enhances proliferation, migration and invasion of pancreatic cancer cells.•Nicotine exhibits the above effects via nAChR-mediated signaling.•Nicotine facilitates aPKC accumulation in the plasma membrane.•Nicotine enhances activation of the kinase activity of aPKC.•These changes are accompanied by activation of PI3K signaling.