TY - JOUR
T1 - Nicotine enhances the malignant potential of human pancreatic cancer cells via activation of atypical protein kinase C
AU - Hanaki, Takehiko
AU - Horikoshi, Yosuke
AU - Nakaso, Kazuhiro
AU - Nakasone, Masato
AU - Kitagawa, Yoshinori
AU - Amisaki, Masataka
AU - Arai, Yosuke
AU - Tokuyasu, Naruo
AU - Sakamoto, Teruhisa
AU - Honjo, Soichiro
AU - Saito, Hiroaki
AU - Ikeguchi, Masahide
AU - Yamashita, Kazunari
AU - Ohno, Shigeo
AU - Matsura, Tatsuya
N1 - Funding Information:
This work was supported by JSPS KAKENHI Grant Numbers 23790379 (YH), 24591262 (KN), 15K09315 (KN), and 15K00816 (TM).
Publisher Copyright:
© 2016 Elsevier B.V.
PY - 2016/11/1
Y1 - 2016/11/1
N2 - 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.
AB - 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.
KW - Atypical protein kinase C
KW - Epithelial-mesenchymal transition
KW - Nicotine
KW - Nicotine acetylcholine receptor
KW - Pancreatic cancer
KW - Phosphatidylinositol 3-kinase
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U2 - 10.1016/j.bbagen.2016.07.008
DO - 10.1016/j.bbagen.2016.07.008
M3 - Article
C2 - 27424921
AN - SCOPUS:84984662480
VL - 1860
SP - 2404
EP - 2415
JO - Biochimica et Biophysica Acta - General Subjects
JF - Biochimica et Biophysica Acta - General Subjects
SN - 0006-3002
IS - 11
ER -