Nicotine induces cell proliferation, invasion and epithelial-mesenchymal transition in a variety of human cancer cell lines.
Cigarette smoking is strongly correlated with the onset of nonsmall cell lung cancer (NSCLC). Nicotine, an active component of cigarettes, has been found to induce proliferation of lung cancer cell lines. In addition, nicotine can induce angiogenesis and confer resistance to apoptosis. All these events are mediated through the nicotinic acetylcholine receptors (nAChRs) on lung cancer cells. In this study, we demonstrate that nicotine can promote anchorage-independent growth in NSCLCs. In addition, nicotine also induces morphological changes characteristic of a migratory, invasive phenotype in NSCLCs on collagen gel. These morphological changes were similar to those induced by the promigratory growth factor VEGF. The proinvasive effects of nicotine were mediated by alpha7-nAChRs on NSCLCs. RT-PCR analysis showed that the alpha7-nAChRs were also expressed on human breast cancer and pancreatic cancer cell lines. Nicotine was found to promote proliferation and invasion in human breast cancer. The proinvasive effects of nicotine were mediated via a nAChR, Src and calcium-dependent signaling pathway in breast cancer cells. In a similar fashion, nicotine could also induce proliferation and invasion of Aspc1 pancreatic cancer cells. Most importantly, nicotine could induce changes in gene expression consistent with epithelial to mesenchymal transition (EMT), characterized by reduction of epithelial markers like E-cadherin expression, ZO-1 staining and concomitant increase in levels of mesenchymal proteins like vimentin and fibronectin in human breast and lung cancer cells. Therefore, it is probable that the ability of nicotine to induce invasion and EMT may contribute to the progression of breast and lung cancers.
Drug Discovery Program, H Lee Moffitt Cancer Center and Research Institute, Tampa, FL 33612, USA.
Piyali
P
Dasgupta
Wasia
W
Rizwani
Smitha
S
Pillai
Rebecca
R
Kinkade
Michelle
M
Kovacs
Shipra
S
Rastogi
Sarmistha
S
Banerjee
Melanie
M
Carless
Esther
E
Kim
Domenico
D
Coppola
Eric
E
Haura
Srikumar
S
Chellappan
D015820:Cadherins / Q000096:biosynthesis; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects*; D004848:Epithelium / Q000378:metabolism*; D005353:Fibronectins / Q000096:biosynthesis; D006801:Humans; D008648:Mesoderm / Q000378:metabolism*; D008954:Models, Biological; D009361:Neoplasm Invasiveness; D009538:Nicotine / Q000494:pharmacology*; D018722:Nicotinic Agonists / Q000494:pharmacology*; D011978:Receptors, Nicotinic / Q000378:metabolism; D012907:Smoking / Q000009:adverse effects*; D014746:Vimentin / Q000096:biosynthesis; D014945:Wound Healing
D015820:Cadherins; D005353:Fibronectins; D018722:Nicotinic Agonists; D011978:Receptors, Nicotinic; D014746:Vimentin; D009538:Nicotine