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...

In humans as well as in other animal species, the ingestion of food provides the fundamental source of energy for various cellular activities. The intake of food and the ability of controlling the plasma levels of substrates for energy production involve complex mechanisms that ensure a constantly adequate supply of metabolites both in the fasting and in the fed state. A number of hormonal peptides released from the gastrointestinal (GI) tract in response to the ingestion of food have been shown to play a critical role in the postprandial control of glucose homeostasis. They are known to act through three main mechanisms of action. These include; (1) stimulation of insulin secretion of pancreatic islet (beta) cells; (2) inhibition of hepatic gluconeogenesis by suppression of glucagon secretion; and (3) inhibition of GI motility. While for some of these hormones all three mechanisms of action are utilized under physiological conditions, others preferentially use one or a combination of two mechanisms for lowering postprandial hyperglycemia. Although the term glucoincretins (or incretins, or insulinotropic hormones) etymologically only describes factors capable of inducing insulin secretion, it is more frequently used to identify a larger class of peptides that, rather than manifesting a specific mechanism of action (i.e., insulin secretion), share the ability of controlling glucose excursion in the fed state (with or without a direct insulinotropic effect). The latter more inclusive meaning, incretins, is used in this article. This review summarizes recent advances on synthesis, secretion, blood plasma patterns, and metabolism of some of the major GI regulatory peptides acting in the postprandial state.