Papers by Hussein Al-Wadei
Cancer, 2008
Background-Pancreatic ductal adenocarcinoma (PDAC) a leading cause of cancer death. Smoking, diab... more Background-Pancreatic ductal adenocarcinoma (PDAC) a leading cause of cancer death. Smoking, diabetes and pancreatitis are risk factors. We have shown that the growth of PDAC and pancreatic duct epithelial cells is regulated by beta-adrenoreceptors (β-ARs). The activity of β-ARs in the central nervous system is counteracted by γ-aminobutyric acid (GABA) via GABA B receptor-mediated inhibition of adenylyl cyclase. The aim of this study was to investigate if the GABA B R inhibits β-AR signaling in PDAC and pancreatic duct epithelial cells, thus blocking driving forces of cancer progression, such as cell proliferation and cell migration. Methods-Intracellular cAMP was measured by immunoassays, DNA synthesis by BRDU incorporation assays, activation of ERK1/2 by ERK activation assays and Western blots and metastatic potential by cell migration assays in the human PDAC cell lines PANC-1 and BXPC-3 and immortalized human pancreatic duct epithelial cells HPDE6-C7. The expression of norepinephrine, PKAR IIα and GABA in PDAC microarrays was assessed by immunohistochemistry. Results-Stimulation of the GABA B R by GABA or baclofen inhibited isoproterenol-induced cAMP signaling below base levels. ERK1/2 activity in response to isoproterenol was blocked by GABA, an effect enhanced by transient overexpression of the GABA B R and abolished by GABA B R knockdown. DNA synthesis and cell migration were stimulated by isoproterenol, responses blocked by GABA and baclofen. Norepinephrine and PKAR IIα were overexpressed while GABA was underexpressed in human PDAC tissue arrays. Conclusions-Our data suggest the stimulation ofGABA B R signaling as a novel target for the treatment and prevention of pancreatic cancer.
Human lung adenocarcinoma (AC) and pancreatic ductal adenocarcinoma (PDAC) are among the most com... more Human lung adenocarcinoma (AC) and pancreatic ductal adenocarcinoma (PDAC) are among the most common types of human cancer and have a poor prognosis in all populations investigated. Smoking is a risk factor for both malignancies. Nicotine addiction is characterized by changes of nicotinic acetylcholine receptors (nAChRs) in the brain to increase the production of excitatory neurotransmitters while reducing inhibitory neurotransmitters. The current study has tested the hypothesis that chronic nicotine stimulates the growth of PAC and PDAC xenografts in nude mice via similar mechanisms. Groups of nude mice carrying xenografts of AC cell line NCI-H322 or PDAC cell line Panc-1 remained untreated, were given nicotine in the drinking water for 30 days in the presence and absence of daily injections with GABA or were treated with GABA alone. The diameters of xenografts were measured. Levels of noradrenaline and adrenaline, the stress hormone cortisol, the neurotransmitter γ-aminobutyric acid (GABA) in serum and xenograft tissues and levels of cAMP in the cellular fraction of blood and in xenograft tissue were assessed by immunoassays. The levels of GAD65, GAD67, nAChRs and signaling proteins downstream of β-ARs in the tumor tissue were determined by Western blotting. Our data show a significant stimulation of xenografts from both cell lines by chronic nicotine that was reversed by treatment with GABA. Nicotine also significantly increased the systemic levels of adrenaline, noradrenaline and cAMP while decreasing GABA. The protein levels of nicotinic acetylcholine receptors α4 and α7, p-CREB and p-ERK1/2 in the tumor tissue was significantly increased by nicotine and reversed by GABA. Nicotine additionally reduced the protein levels of both GAD isozymes in tumor tissue. In summary, our findings suggest that nicotine-induced predominance of stimulatory noradrenaline and deficiency in inhibitory GABA similar to nicotine-addiction in the brain may contribute to the development of lung adenocarcinoma in smokers and that GABA may be useful for marker-guided prevention and adjuvant therapy for PAC and PDAC. Supported by R01 CA042829 and R01 CA130888 with National Institutes of Health. Citation Information: Cancer Prev Res 2010;3(12 Suppl):A6.
Smoking is an established risk factor for pancreatic cancer. More than 95% of all pancreatic canc... more Smoking is an established risk factor for pancreatic cancer. More than 95% of all pancreatic cancers are pancreatic ductal adenocarcinomas (PDACs). Our data has earlier established that nicotine contributes to the progression of smoking associated PDAC by increasing the systemic levels of the stress neurotransmitters adrenaline and noradrenaline in pancreatic cancer xenografts. These findings suggested that development and progression of PDAC is subject to significant modulation by stimulatory stress neurotransmitters. Here we demonstrate that nicotine abrogates the apoptotic activity of gemcitabine, gefitinib, and meloxicam, which are standard therapy for PDAC, in a variety of human PDAC cell lines. We first evaluated the effect of gemcitabine, gefitinib and meloxicam on cell proliferation using a varied range of concentrations and timepoints on pancreatic cancer cell lines PANC-1 and BXPC-3. The results demonstrated that all the three anti-cancer drugs significantly inhibited the proliferation of pancreatic cancer cells PANC-1 and BXPC-3. The IC50 values were determined for optimal concentration and timepoint. It was next examined whether chronic nicotine could confer protection against apoptosis induced by gemcitabine, gefitinib, and meloxicam, which are widely used to treat PDAC. Cells were stimulated with 1 µM nicotine (pre-determined concentration) in the presence or absence of the IC50 concentrations of the indicated drugs. Our results indicated that nicotine suppresses apoptosis induced by gemcitabine, gefitinib, and meloxicam in pancreatic cancer cells, as measured by TUNEL assays, viability assays and western blotting of apoptosis associated proteins. In conclusion, the antiapoptotic effects of nicotine, negatively impacts the chemosensitivity of PDAC cells against anticancer drugs. These findings suggest that continued exposure to nicotine during cancer therapy may significantly reduce the responsiveness to anti-cancer agents. This work is supported by grants RO1CA130888 and RO1CA042829 with the National Cancer Institute. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 1010. doi:10.1158/1538-7445.AM2011-1010
Pancreatic ductal adenocarinoma (PDAC) is a leading cause of cancer deaths in developed countries... more Pancreatic ductal adenocarinoma (PDAC) is a leading cause of cancer deaths in developed countries. The nucleoside analog Gemcitabine, which induces apoptosis, is widely used for the therapy of pancreatic cancer. Smoking and alcoholism are risk factors for pancreatic cancer. Nicotine replacement therapy often accompanies chemotherapy while the GABA-B receptor (GABA-B-R) agonist Baclofen has recently been suggested as an effective agent for the treatment of alcohol dependence. Our laboratory has shown that the proliferation and migration of PDAC and pancreatic duct epithelial cells in vitro is regulated by the nicotinic receptor-mediated synthesis and release of stress neurotransmitters that bind to beta-adrenoreceptors (beta-ARs). We have additionally shown that nicotine in the drinking water at a high dose (432 μmole/L) comparable to nicotine exposure in heavy smokers significantly stimulated the growth of PDAC xenografts whereas identical exposure of mice to low dose nicotine (1 μmole/L) reduced gemcitabine-induced apoptosis, thus significantly increasing resistance to gemcitabine. In the current study, we have investigated the potential prevention of nicotine-induced gemcitabine resistance by γ-aminobutyric acid (GABA) and Baclofen in PDAC xenografts. We found that GABA significantly reduced nicotine-induce drug resistance. By contrast, Baclofen failed to reduce nicotine-induced resistance to gemcitabine while even slightly increasing xenograft growth in mice not exposed to nicotine. Investigation of xenograft tissues for the expression levels of the GABA-B-R, intracellular cAMP and signaling proteins associated with cell proliferation, apoptosis and metastasis by immunoassays and western blots revealed effective inhibition of cAMP-dependent signaling in xenografts of mice treated with GABA. By contrast, Baclofen did not inhibit cAMP-dependent signaling and decreased the protein expression of the GABA-R, suggesting downregulation of the receptor. Our findings identify GABA as a promising agent for the prevention of nicotine-induced resistance to gemcitabine in PDAC. On the other hand, our data suggest that treatment of alcohol dependence by Baclofen should be avoided in PDAC patients. Supported by grants RO1CA130888 and RO1CA042829 with the National Cancer Institute. Citation Format: Jheelam Banerjee, Mohammed H. Al-Wadei, Hussein A. N. Al-Wadei, Hildegard M. Schuller. GABA but not baclofen prevents gemcitabine resistance induced by low dose nicotine in pancreatic cancer xenografts. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 2191. doi:10.1158/1538-7445.AM2013-2191
PLOS ONE, Jan 12, 2012
Lung cancer is the leading cause of cancer death; 80-85% of lung cancer cases are non-small cell ... more Lung cancer is the leading cause of cancer death; 80-85% of lung cancer cases are non-small cell lung cancer (NSCLC). Smoking is a documented risk factor for the development of this cancer. Although nicotine does not have the ability to initiate carcinogenic events, recent studies have implicated nicotine in growth stimulation of NSCLC. Using three NSCLC cell lines (NCI-H322, NCI-H441 and NCI-H1299), we identified the cooperation of nicotinic acetylcholine receptors (nAChRs) and b-adrenergic receptors (b-ARs) as principal regulators of these effects. Proliferation was measured by thymidine incorporation and MTT assays, and Western blots were used to monitor the upregulation of the nAChRs and activation of signaling molecules. Noradrenaline and GABA were measured by immunoassays. Nicotine-treated NSCLC cells showed significant induction of the a7nAChR and a4nAChR, along with significant inductions of p-CREB and p-ERK1/2 accompanied by increases in the stress neurotransmitter noradrenaline, which in turn led to the observed increase in DNA synthesis and cell proliferation. Effects on cell proliferation and signaling proteins were reversed by the a7nAChR antagonist a-BTX or the b-blocker propranolol. Nicotine treatment also down-regulated expression of the GABA synthesizing enzyme GAD 65 and the level of endogenous GABA, while treatment of NSCLC cells with GABA inhibited cell proliferation. Interestingly, GABA acts by reducing b-adrenergic activated cAMP signaling. Our findings suggest that nicotine-induced activation of this autocrine noradrenaline-initiated signaling cascade and concomitant deficiency in inhibitory GABA, similar to modulation of these neurotransmitters in the nicotine-addicted brain, may contribute to the development of NSCLC in smokers. Our data suggest that exposure to nicotine either by tobacco smoke or nicotine supplements facilitates growth and progression of NSCLC and that pharmacological intervention by b blocker may lower the risk for NSCLC development among smokers and could be used to enhance the clinical outcome of standard cancer therapy.
Current Cancer Drug Targets, Feb 1, 2012
Carcinogenesis, Nov 9, 2011
Pancreatic cancer has a poor prognosis and is associated with high levels of psychological stress... more Pancreatic cancer has a poor prognosis and is associated with high levels of psychological stress that may adversely affect clinical outcomes. However, the potential influence of neuropsychological factors on pancreatic cancer has not been investigated to date. Using a mouse model of social stress, we have tested the hypothesis that psychological stress promotes the progression of pancreatic cancer xenografts via neurotransmitter-induced activation of multiple pathways and that the inhibitory neurotransmitter g-aminobutiric acid (GABA) inhibits these responses. Sytemic and xenograft levels of noradrenalin, adrenalin, GABA, cortisol, vascular endothelial growth factor (VEGF) and cyclic adenosine 3#, 5#-monophosphate (cAMP) were measured by immunoassays. Xenograft expression of nicotinic acetylcholine receptors (nAChRs) a3, a4, a5, a6 and a7 and b-adrenergic receptors 1 and 2 were assessed by real-time PCR and western blots. Expression of glutamate decarboxylases GAD65 and GAD67 and phosphorylated and unphosphorylated signaling proteins of relevance to pancreatic cancer were determined in tumor tissue by western blots. Psychological stress significantly promoted xenograft growth and increased systemic and tumor levels of noradrenalin, adrenalin, cortisol, VEGF and cAMP while GABA and GAD were suppressed. Stress upregulated nAChR proteins but not RNAs and induced phosphorylated ERK, CREB, Src and AKT in xenografts. Reduction of cAMP by treatment with GABA prevented tumor progression and activation of signaling proteins. Our findings suggest that neurotransmitter responses to psychological stress negatively impact clinical outcomes of pancreatic cancer via the activation of multiple pathways and that replacement of the suppressed inhibitory neurotransmitter GABA prevents these effects. Ã Data are mean values and standard errors of fold changes (n 5 5). Significant differences (by unpaired two-tailed t-test) are identified by asterix.
Cancer Research, May 1, 2005
6081 Numerous laboratory studies have shown that the pro-vitamin beta-carotene inhibits the devel... more 6081 Numerous laboratory studies have shown that the pro-vitamin beta-carotene inhibits the development of cancer from upper airway epithelia. However, in clinical trials it increased mortality from lung cancer and cardiovascular disease. Our studies in human pulmonary adenocarcinoma cells (PAC) and their putative cells of origin, small airway epithelial cells (SAEC), show that beta-carotene (1 pM to 200 nM) stimulated the growth of both cell systems as monitored by MTT assays. By contrast, beta-carotene inhibited the growth of human large airway epithelial cells. Using immunoassays, PKA activation assays and Western blots, we provide evidence suggesting that the proliferative response of SAEC and PAC to beta-carotene was mediated via an increase in intracellular cAMP and activation of PKA, CREB and ERK1/2.These findings suggest that beta-carotene may selectively promote the development of PAC and should not be used as chemopreventive agent. The growth stimulating effects of beta-carotene on SAEC and PAC may have caused the unfortunate outcome of clinical trials with this agent. Moreover, our findings are the first report that links the activation of PKA/CREB with the growth regulation of a specific type of lung cancer. Our findings are in accord with our recent discovery that beta-adrenergic agonists and the cAMP activator forskolin promote the growth of PAC in vitro and in a hamster model in vivo.
Molecular Cancer Research, Feb 1, 2012
Pancreatic cancer is the fourth leading cause of cancer deaths in developed countries. Smoking is... more Pancreatic cancer is the fourth leading cause of cancer deaths in developed countries. Smoking is an established risk factor for this malignancy but the underlying mechanisms are poorly understood. Previous reports have provided evidence that nicotinic acetylcholine receptors (nAChR) and beta adrenergic receptors (b-AR) stimulate the growth and migration of pancreatic cancer cells. However, a potential cooperation of these two receptor families in the regulation of pancreatic cancer has not been studied to date. Using two pancreatic cancer cell lines and immortalized pancreatic duct epithelia in vitro, our current data show that all three cell lines synthesized and released the catecholamine neurotransmitters noradrenaline and adrenaline upon exposure to nicotine and that this activity was regulated by a3, a5, and a7-nAChRs. In accordance with the established function of these catecholamines as bAR agonists, nicotine-induced cell proliferation was blocked by the bAR antagonist propranolol. Nicotineinduced proliferation was also abolished by the a7-nAChR antagonist a-bungarotoxin, whereas catecholamine production in response to nicotine was blocked by gene knockdown of the a3, a5, and a7-nAChRs. The nicotinic agonists acetylcholine, nicotine, and its nitrosated carcinogenic derivative NNK induced the phosphorylation of CREB, ERK, Src, and AKT and these responses were inhibited by propranolol. Our findings identify this hitherto unknown autocrine catecholamine loop as an important regulatory cascade in pancreatic cancer that may prove a promising new target for cancer intervention. Mol Cancer Res; 10(2); 239-49. Ó2011 AACR.
Cancer Research, May 1, 2009
Small airway-derived pulmonary adenocarcinoma (PAC) and pancreatic ductal adenocarcinoma (PDAC) a... more Small airway-derived pulmonary adenocarcinoma (PAC) and pancreatic ductal adenocarcinoma (PDAC) are common human cancers and smoking is a risk factor for both. Emerging research has identified cAMP signaling stimulated by the stress neurotransmitters adrenaline and noradrenaline as stimulators of PAC and PDAC. We have shown that the inhibitory neurotransmitter \#947;-aminobutyric acid (GABA) blocks the cAMP-dependent proliferation and migration of PAC and PDAC cells in vitro. The nicotine-derived nitrosamine 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) is a potent mutagen and carcinogen. NNK is also an agonist for nicotinic acetylcholine receptors (nAChRs). These receptors are central regulators that control the synthesis and release of neurotransmitters, growth factors, angiogenic factors and inflammatory mediators. The alpha7-nAChR stimulates the synthesis and release of adrenaline and noradrenaline in the brain and from nerve endings in all organs and tissues. The alpha4beta2-nAChR stimulates the synthesis and release of GABA that is expressed in most mammalian cells. While signal transduction events downstream of nAChRs expressed in cancer cells have been extensively studied, the systemic effects of these receptors on cancer have been largely ignored. Using hamster models of NNK-induced PAC and PDAC, we have tested the hypothesis that in analogy to chronic effects of nicotine in the brain, NNK may modulate the alpha7 and alpha4beta2-nAChR, causing a systemic increase in stress neurotransmitters and decrease in GABA. In support of our hypothesis, we found significant increase in serum adrenaline/noradrenaline and increased cAMP in the cellular fraction of blood from NNK treated hamsters. The GABA synthesizing enzyme glutamate decaboxylase 65 (GAD65) and GABA were suppressed in NNK-induced PACs and PDACs, whereas protein expression of the alpha7nAChR, alpha4-nAChR as well as p-CREB and p-ERK1/2 were upregulated. In analogy to the chronic effects of nicotine on brain cells, these data suggest that chronic exposure to NNK upregulates both investigated nAChRs while additionally desensitizing the alpha4beta2-nAChR, resulting in increased levels of cancer stimulating stress neurotransmitters and suppressed inhibitory GABA. Collectively, these findings suggest, for the first time, that NNK-induced alterations in regulatory nAChRs may contribute to the development of smoking-associated PAC and PDAC by disturbing the systemic balance between cancer stimulating and inhibiting neurotransmitters. Citation Information: In: Proc Am Assoc Cancer Res; 2009 Apr 18-22; Denver, CO. Philadelphia (PA): AACR; 2009. Abstract nr 2507.
Current Cancer Therapy Reviews, 2012
Psychologic distress is associated with increased lung cancer incidence and mortality. We have sh... more Psychologic distress is associated with increased lung cancer incidence and mortality. We have shown that non–small cell lung cancer (NSCLC) cells in vitro are stimulated by the cyclic AMP (cAMP)-dependent activation of cAMP-responsive element binding protein (CREB) and extracellular signal–regulated kinase (ERK) downstream of β-adrenergic receptors and that this pathway is inhibited by the neurotransmitter γ-aminobutyric acid (GABA). Because the stress neurotransmitters noradrenalin and adrenalin are β-adrenergic agonists, the current study has tested the hypothesis that social stress stimulates NSCLC growth in vivo and that GABA inhibits this effect. Social stress was induced in mice carrying xenografts from two NSCLC cell lines in the presence and absence of treatment with GABA. Xenograft sizes were measured after 30 days. Noradrenalin, adrenalin, cortisol, GABA, and cAMP were measured in blood and tumor tissues by immunoassays. Expression of nicotinic receptors in the xenografts...
Lung cancer is the leading cause of cancer mortality for men and women in the United States, with... more Lung cancer is the leading cause of cancer mortality for men and women in the United States, with a high mortality rate and a five-year survival rate of less than 15%.Cancer ranks second as a cause of death for Americans after cardiovascular disease. The American Cancer Society (ACS) reported 171,900 new cases of lung cancer for 2003 (ACS, 2003). Peripheral adenocarcinoma (PAC) of the lung has increased dramatically over the last 20 years and is the leading histological type of lung cancer in smokers and nonsmokers in industrialized countries, including the United States. Among the four main histological lung caner types (small-cell carcinoma, squamous-cell carcinoma, adenocarcinoma and large-cell carcinoma), adenocarcinoma that is derived from small airway epithelia with features of Clara cells accounts for about 35-40% of all lung cancer cases. Unlike other .. histological lung cancer types, adenocarcinoma also develops in a significant number of non-smokers. Smoking remains the ...
Cancer Research, 2014
Pancreatic cancer is frequently resistant to cancer therapeutics. Smoking and alcoholism are risk... more Pancreatic cancer is frequently resistant to cancer therapeutics. Smoking and alcoholism are risk factors and pancreatic cancer patients often undergo nicotine replacement therapy (NRT) and treatment for alcohol dependence. Based on our report that low dose nicotine within the range of NRT causes gemcitabine resistance in pancreatic cancer, our current study has tested the hypothesis that GABA or the selective GABA-B-R agonist baclofen used to treat alcohol dependence reverse nicotine-induced gemcitabine resistance in pancreatic cancer. Using pancreatic cancer cell lines BXPC-3 and PANC-1, our data show that GABA significantly reversed gemcitabine resistance induced by low dose nicotine in xenografts whereas baclofen did not. This effect of GABA was accompanied by decreases in cAMP, p-CREB, p-AKT, p-Src, p-ERK metalloproteinases-9 and -2 and EGR-1 and increases in cleaved caspase-3 in xenografts whereas baclofen had the opposite effects. In vitro exposure of cells to single doses or...
Carcinogenesis, 2012
Pancreatic ductal adenocarcinoma (PDAC) has a mortality rate near 100%. Smoking is a documented r... more Pancreatic ductal adenocarcinoma (PDAC) has a mortality rate near 100%. Smoking is a documented risk factor. However, the mechanisms of smoking-associated pancreatic carcinogenesis are poorly understood. We have shown that binding of nicotine to nicotinic acetylcholine receptors (nAChRs) expressing subunits α7, α3 and α5 in PDAC and pancreatic duct epithelial cells in vitro triggered the production of the neurotransmitters noradrenaline and adrenaline by these cells. In turn, this autocrine catecholamine loop significantly stimulated cell proliferation via cyclic adenosine 3ʹ,5ʹ-monophosphate-dependent signaling downstream of beta-adrenergic receptors. However, the observed responses only represent acute cellular reactions to single doses of nicotine whereas nicotine exposure in smokers is chronic. Using the PDAC cell lines BxPC-3 and Panc-1 and immortalized pancreatic duct epithelial cell line HPDE6-C7, our current experiments reveal a significant sensitization of the nAChR-driven autocrine catecholamine regulatory loop in cells pre-exposed to nicotine for 7 days. The resulting increase in catecholamine production was associated with significant inductions in the phosphorylation of signaling proteins ERK, CREB, Src and AKT, upregulated protein expression of nAChR subunits α3, α4, α5 and α7 and increased responsiveness to nicotine in 3-(4,5-dimethylthiazole-2-yl)-2,5-diphenyl tetrazolium bromide and cell migration assays. All three cell lines produced the inhibitory neurotransmitter γ-aminobutyric acid, an activity inhibited by gene knockdown of the α4β2nAChR and suppressed by chronic nicotine via receptor desensitization. All of the observed adverse effects of chronic nicotine were reversed by treatment of the cells with γ-aminobutyric acid, suggesting the potential usefulness of this agent for the improvement of PDAC intervention strategies in smokers.
Pancreatic cancer is an aggressive disease with poor diagnosis and prognosis. The absence of effe... more Pancreatic cancer is an aggressive disease with poor diagnosis and prognosis. The absence of effective screening tests to detect this malignancy at an early stage is one of the factors responsible for its metastasis. Patients suffering from pancreatic cancer do not show any symptoms until it has reached an advanced stage upon which it has spread to distant organs thereby eliminating surgery as a possible option for therapy. Up to date, there are no effective treatments for pancreatic cancer which makes pancreatic cancer a deadly disease with a 5 year survival rate of less than 5 %. With these horrifying statistics, research on pancreatic cancer took a different approach in studying the mechanisms of this malignancy. While research on the past focused on gene mutations and their downstream signaling pathways, recently, research started to look at upstream receptors such as nicotinic acetylcholine receptors and how they may be involved in regulating growth of this malignancy. Nicotinic acetylcholine receptors (nAChRs) are a family of plasma membrane, ionotropic receptors consisting of five subunits. While these receptors were previously thought to be restricted to the nervous system, recent studies have found them to be expressed in most mammalian cells including those of the pancreas. Binding of these receptors to their agonists result in the activation of their associated ion channels which results in several cellular changes including neurotransmitters production. Among the neurotransmitters whose production increase upon activation of the nAChRs are the catecholamine, adrenaline and noradrenaline. Brief explanatory statement This chapter is a slightly revised version of a manuscript that has been accepted for publication in "Carcinogenesis" on July 2012.
Molecular Cancer Therapeutics, 2007
B203 Pulmonary adenocarcinoma (PAC) and pancreatic ductal adenocarcinoma (PDAC) are among the mos... more B203 Pulmonary adenocarcinoma (PAC) and pancreatic ductal adenocarcinoma (PDAC) are among the most common human malignancies and are highly resistant to conventional cancer therapy. We have shown that both cancers respond to beta-adrenergic stimulation by cAMP-dependent signaling via PKA/CREB and PKA-dependent transactivation of the EGFR, resulting in stimulation of cell proliferation and migration and that the tobacco carcinogen NNK activates these signaling cascades. Our current data show that the neurotransmitter gamma-amino-butyric acid (GABA) completely abrogates this cAMP-dependent proliferation and migration of PAC and PDAC cells and their normal cells of origin (small airway epithelial cells and pancreatic duct epithelial cells). These effects of GABA were mediated by the Galphai-coupled GABA-B receptor as evidenced by GABA-B knockdown in Western blots and luciferase reporter assays for the identification of activated CREB and ERK1/2 and also reduced base level proliferation...
Cancer genomics & proteomics
Pancreatic ductal adenocarcinoma (PDAC) is among the most common causes of cancer death. Preclini... more Pancreatic ductal adenocarcinoma (PDAC) is among the most common causes of cancer death. Preclinical and clinical studies on the preventive effects of beta-carotene or other retinoids have used dietary supplements that yielded high systemic concentrations (1-50 microM). While some of the preclinical data suggested cancer preventive effects of these agents, they have disappointed in clinical investigations. The effects of low concentrations (10 fM-200 nM)of beta-carotene on the proliferation, intracellular cAMP levels, PKA activation status and phosphorylation of EGFR-specific tyrosine kinases and ERK1/2 in immortalized human pancreatic duct epithelial cells was investigated. Our data show significant concentration-dependent and PKA-dependent stimulation of all measured endpoints. Similar responses were achieved with forskolin. Our data indicate that low concentrations of beta-carotene stimulate the proliferation of the putative origin of PDAC, pancreatic duct epithelial cells via cA...
International Journal of Oncology - INT J ONCOL, 2009
Studies have suggested that retinoids prevent lung cancer by interacting with nuclear retinoid re... more Studies have suggested that retinoids prevent lung cancer by interacting with nuclear retinoid receptors. However, clinical trials with β-carotene increased lung cancer mortality. We recently showed that β-carotene stimulates the proliferation of small airway-derived adenocarcinoma by increasing cAMP signaling. Here, we have tested the hypothesis that β-carotene may stimulate squamous cell carcinoma cells via similar mechanisms. We determined the effects of β-carotene in cell lines from squamous cell carcinomas and large airway epithelia on proliferation by MTT assays in the presence and absence of inhibitors. Signaling via cAMP/PKA was measured by immunoassays and PKA activation assay. Phosphorylated ERK1/2 was determined by Western blotting. β-carotene significantly inhibited proliferation and phosphorylation of ERK1/2 by Gαs-mediated signaling involving adenylyl cyclase, cAMP, PKA and ERK1/2. These findings introduce a non-genomic inhibitory mechanism of β-carotene and emphasize ...
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Papers by Hussein Al-Wadei