Nicotine Induces Cyclooxygenase-2 and Vascular Endothelial Growth Factor Receptor-2 in Association with Tumor-Associated Invasion and Angiogenesis in Gastric Cancer

Tang

Clinical Cancer Research

et al. 2007

140

106

Purpose: Nicotine, the major component in cigarette smoke, can promote tumor growth and angiogenesis in various cancers, including lung cancer. Hypoxia-inducible factor-1a (HIF-1a) 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-1a and VEGF using Western blot or ELISA. Loss of HIF-1a function using specific small interfering RNA was used to determine whether HIF-1a is directly involved in nicotine-induced tumor angiogenic activities, including VEGF expression, cancer cell migration, and invasion. Results: Nicotine increased HIF-1a and VEGF expression in NSCLC cells. Pharmacologically blocking nicotinic acetylcholine receptor^mediated signaling cascades, including the Ca 2+ / 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-1a 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-1a. Conclusion: These findings identify novel mechanisms by which nicotine promotes tumor angiogenesis and metastasis and provide further evidences that HIF-1a is a potential anticancer target in nicotine-associated lung cancer.Worldwide, lung cancer remains the leading cause of cancer death in both men and women, with an estimated 1.2 million deaths annually, of which non -small cell lung cancer (NSCLC) accounts for 75% to 80% of deaths (1). Nicotine, a psychoactive/addictive compound in cigarette smoke and the major risk factor for lung cancer (2, 3), can promote cell proliferation in several tumor cell lines, including SCLC, NSCLC, gastric cancer, pancreatic cancer, and head and neck cancer, via multiple signaling pathways (4 -8). Nicotine has been shown to protect cancer cells from apoptosis induced by diverse stimuli, such as opioid, tumor necrosis factor, UV light, chemotherapeutic drugs, and serum deprivation (5, 8 -12). Moreover, several studies have reported that nicotine exerts proangiogenic activities in tumor xenografts and chick chorioallantoic membrane model of angiogenesis (6, 13 -15). These studies indicate that nicotine possesses both tumor-promoting and angiogenic activities conducive to a more aggressive tumor phenotype. However, the mechanisms underlying nicotinestimulated angiogenesis remain largely unknown.Hypoxia-inducible fact...

Section: Discussionmentioning

confidence: 99%

Nicotine Induces Hypoxia-Inducible Factor-1α Expression in Human Lung Cancer Cells via Nicotinic Acetylcholine Receptor–Mediated Signaling Pathways

Tang

Clinical Cancer Research

et al. 2007

140

106

The Journal of Immunology

“…Although in neurons, the ␣7-nAChRs participate in neurotransmission which is blocked by ␣-bungarotoxin (␣-BTX) and methyllycaconitine (MLA) (16,17), it is unlikely that these receptors perform such a function in nonexcitable cells. Chronic in vivo nicotine treatment suppresses the immune and inflammatory responses (18 -20), causing T cell anergy (21) and decreased leukocyte migration; however, acute exposure to nicotine increases intracellular calcium [Ca 2ϩ ] i and cell migration in several cell types (18,14,22,23). In vivo, nicotine regulates T cell function by direct interaction with T cells and indirectly through neuroimmune interactions (18,24).…”

Section: T He Nicotinic Acetylcholine Receptors (Nachrs)mentioning

confidence: 99%

T Cells Express α7-Nicotinic Acetylcholine Receptor Subunits That Require a Functional TCR and Leukocyte-Specific Protein Tyrosine Kinase for Nicotine-Induced Ca2+ Response

Razani‐Boroujerdi

Boyd

Dávila‐García

et al. 2007

157

132

Acute and chronic effects of nicotine on the immune system are usually opposite; acute treatment stimulates while chronic nicotine suppresses immune and inflammatory responses. Nicotine acutely raises intracellular calcium ([Ca2+]i) in T cells, but the mechanism of this response is unclear. Nicotinic acetylcholine receptors (nAChRs) are present on neuronal and non-neuronal cells, but while in neurons, nAChRs are cation channels that participate in neurotransmission; their structure and function in nonexcitable cells are not well-defined. In this communication, we present evidence that T cells express α7-nAChRs that are critical in increasing [Ca2+]i in response to nicotine. Cloning and sequencing of the receptor from human T cells showed a full-length transcript essentially identical to the neuronal α7-nAChR subunit (>99.6% homology). These receptors are up-regulated and tyrosine phosphorylated by treatment with nicotine, anti-TCR Abs, or Con A. Furthermore, knockdown of the α7-nAChR subunit mRNA by RNA interference reduced the nicotine-induced Ca2+ response, but unlike the neuronal receptor, α-bungarotoxin and methyllycaconitine not only failed to block, but also actually raised [Ca2+]i in T cells. The nicotine-induced release of Ca2+ from intracellular stores in T cells did not require extracellular Ca2+, but, similar to the TCR-mediated Ca2+ response, required activation of protein tyrosine kinases, a functional TCR/CD3 complex, and leukocyte-specific tyrosine kinase. Moreover, CD3ζ and α7-nAChR coimmunoprecipitated with anti-CD3ζ or anti-α7-nAChR Abs. These results suggest that in T cells, α7-nAChR, despite its close sequence homology with neuronal α7-nAChR, fails to form a ligand-gated Ca2+ channel, and that the nicotine-induced rise in [Ca2+]i in T cells requires functional TCR/CD3 and leukocyte-specific tyrosine kinase.

Molecular Cancer Therapeutics

“…Nicotine exerts its biologic function mainly through nicotinic acetylcholine receptors (nAChR), b-adrenoreceptors (b-AR), and/or EGF receptors (EGFR) in the motor endplates of muscle and the nervous system (11)(12)(13). The nAChR is also expressed in various cancer cells (14,15). Recent studies have demonstrated that nicotine regulates multiple signaling proteins, especially phospho-specific Akt (pAkt) in lung, oral, and breast cancer cells (16)(17)(18)(19).…”

Section: Introductionmentioning

confidence: 99%

Nicotine Induces Tumor Growth and Chemoresistance through Activation of the PI3K/Akt/mTOR Pathway in Bladder Cancer

Yuge

Kikuchi

Yasumizu

et al. 2015

Continued smoking is highly associated with not only a higher incidence but also greater risk of tumor recurrence, progression, and acquired chemoresistance of urothelial carcinoma. We investigated whether nicotine affects urothelial carcinoma, and the detailed mechanism by which nicotine could induce tumor growth and any associated chemoresistance. Cell viability was evaluated in the human bladder cancer cell line T24 exposed to nicotine with or without cisplatin (CDDP) and NVP-BEZ235 as a PI3K/mTOR dual inhibitor by the WST-1 assay. Protein expression of the PI3K/Akt/mTOR pathway was investigated by Western blotting or immunohistochemical analysis. The influence of nicotine on tumor growth was also evaluated with or without CDDP and/or NVP-BEZ235 in a subcutaneous bladder tumor model. The result demonstrated that cell proliferation was increased in T24 cells after exposure to nicotine. Phospho-specific Akt (pAkt) and phospho-specific p70 S6 kinase (pS6) were significantly upregulated by nicotine exposure. Tumor growth in vivo was significantly induced by nicotine exposure in accordance with increased pS6 expression. Nicotine attenuated inhibition of T24 cell growth by CDDP and further upregulated pS6 expression in vitro and in vivo. NVP-BZE235 inhibited T24 cell proliferation and pAkt and pS6 expression induced after exposure to nicotine and/or CDDP. In conclusion, nicotine increases tumor growth and induces acquired chemoresistance through activation of the PI3K/Akt/mTOR pathway in bladder cancer.