Departmental Papers (Dental)
Nicotine Induces Hypoxia-Inducible Factor-1AExpression in Human Lung Cancer Cells via Nicotinic Acetylcholine Receptor ^Mediated Signaling Pathways
Date of this Version
Clinical Cancer Research
Purpose: Nicotine, the major component in cigarette smoke, can promote tumor growth and angiogenesis in various cancers, including lung cancer. Hypoxia-inducible factor-1α (HIF-1α) is overexpressed in human lung cancers, particularly in non - small cell lung cancers (NSCLC), and is closely associated with an advanced tumor grade, increased angiogenesis, and resistance to chemotherapy and radiotherapy. The purpose of this study was to investigate the effects of nicotine on the expression of HIF-1aand its downstream target gene, vascular endothelial growth factor (VEGF), in human lung cancer cells. Experimental Design: Human NSCLC cell lines A549 and H157 were treated with nicotine and examined for expression of HIF-1α and VEGF using Western blot or ELISA. Loss of HIF-1α function using specific small interfering RNA was used to determine whether HIF-1α is directly involved in nicotine-induced tumor angiogenic activities, including VEGF expression, cancer cell migration, and invasion. Results: Nicotine increased HIF-1α and VEGF expression in NSCLC cells. Pharmacologically blocking nicotinic acetylcholine receptor - mediated signaling cascades, including the Ca2+/ calmodulin, c-Src, protein kinase C, phosphatidylinositol 3-kinase, mitogen-activated protein kinase/extracellular signal-regulated kinase 1/2, and the mammalian target of rapamycin pathways, significantly attenuated nicotine-induced up-regulation of HIF-1α protein. Functionally, nicotine potently stimulated in vitro tumor angiogenesis by promoting tumor cell migration and invasion. These proangiogenic and invasive effects were partially abrogated by treatment with small interfering RNA specific for HIF-1α. Conclusion: These findings identify novel mechanisms by which nicotine promotes tumor angiogenesis and metastasis and provide further evidences that HIF-1α is a potential anticancer target in nicotine-associated lung cancer. © 2007 American Association for Cancer Research.
MeSH: 1-Phosphatidylinositol 3-Kinase, Carcinoma, Non-Small-Cell Lung, Cell Line, Tumor, Cell Movement, Humans, Hypoxia-Inducible Factor 1, alpha Subunit, Lung Neoplasms, Neoplasm Invasiveness, Nicotine, Receptors, Nicotinic, RNA, Small Interfering, Signal Transduction, Vascular Endothelial Growth Factor A EMTREE drug terms: hypoxia inducible factor 1alpha, mammalian target of rapamycin, mitogen activated protein kinase, mitogen activated protein kinase 1, mitogen activated protein kinase 3, nicotine, nicotinic receptor, phosphatidylinositol 3 kinase, protein kinase (calcium, calmodulin), protein kinase C, protein tyrosine kinase, small interfering RNA, vasculotropin EMTREE medical terms: angiogenesis, article, cancer cell, cell invasion, cell migration, controlled study, enzyme linked immunosorbent assay, gene targeting, human, human cell, in vitro study, lung non small cell cancer, priority journal, protein analysis, protein depletion, protein expression, protein function, signal transduction, tumor vascularization, upregulation, Western blotting
Zhang, Q., Tang, X., Zhang, Z., Velikina, R., Shi, S., & Le, A. D. (2007). Nicotine Induces Hypoxia-Inducible Factor-1AExpression in Human Lung Cancer Cells via Nicotinic Acetylcholine Receptor ^Mediated Signaling Pathways. Clinical Cancer Research, 13 (16), 4686-4694. http://dx.doi.org/10.1158/1078-0432.CCR-06-2898
Date Posted: 10 February 2023
This document has been peer reviewed.
At the time of publication, author Qunzhou Zhang was affiliated with the Center for Craniofacial Molecular Biology, University of Southern California School of Dentistry. Currently, (s)he is a faculty member at the School of Dental Medicine at the University of Pennsylvania.
At the time of publication, author Shihong Shi was affiliated with the Center for Craniofacial Molecular Biology, University of Southern California School of Dentistry. Currently, (s)he is a faculty member at the School of Dental Medicine at the University of Pennsylvania.
At the time of publication, author Anh D. Le was affiliated with the Center for Craniofacial Molecular Biology, University of Southern California School of Dentistry. Currently, (s)he is a faculty member at the School of Dental Medicine at the University of Pennsylvania.