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At least 307 records · Page 17Linked to original sources
PubMed2006

Site specific differential activation of ras/raf/ERK signaling in rabbit isoproterenol-induced left ventricular hypertrophy.

To understand better the mediating role of ras/raf/ERK signaling pathway in development of cardiac hypertrophy and cerebrovascular events in vivo, the molecular mechanism of the pathway in heart and cerebral arteries after isoproterenol (ISO) induced beta-adrenergic receptor (betaAR) stimulation was examined in rabbit as animal model. Compared with the heart, our findings indicate that ISO-stimulation results in increase in mRNA levels of ras, raf, and immediate-early genes in the cerebral arteries. Conversely, the ras and raf protein expression levels (determined by Western blot) and the ras-GTP level (determined by pull-down assay) in the heart, but not the cerebral arteries, are markedly elevated after treatment. In addition, despite constant ERK1/2 abundance, phosphorylated ERK (pERK) activity was elevated at both sites with prominent effect on heart following stimulation. Opposing to the PKA and PKC, as upstream contributors in the pathway, which seem to be similarly affected at both sites following ISO-stimulation, the results imply that the downstream candidates ras and raf, as well as immediate-early genes, have different responses at both sites post-stimulation. The results provide an evidence of site-dependent differential response of ras/raf/ERK pathway after cardiac hypertrophy-induced by ISO-stimulation. This varied response may account for underlying mechanisms of development of cardiac hypertrophy and cerebrovascular events in heart and cerebral arteries, respectively.

Adrenergic beta-Agonists↗
PubMed2004

The physiological unfolded protein response in the thyroid epithelial cells.

The perturbation of the endoplasmic reticulum (ER) homeostasis by the pharmacological agents or mutant secretory proteins invokes the adaptive cellular reaction, unfolded protein response (UPR). Here we show the activation of UPR under the physiological conditions of the hormone-stimulated expression of thyroglobulin (Tg), the major secretory product of thyroid cells. The early increase in the Tg synthesis within 1h after stimulation apparently triggers UPR as it is evidenced by the activation of ATF6- and PERK-dependent pathways of UPR and subsequent expression of the UPR target genes, ER molecular chaperones. However, little or no activation of the other UPR sensor, IRE1, was observed, as judged by the absence of the spliced mRNA of its downstream effector, transcription factor XBP1. We conclude that the physiological UPR in differentiating thyrocytes differs substantially from the drug-induced stress by its weaker manifestation and distinct pattern of the activation of UPR sensors.

Activating Transcription Factor 6↗
PubMed2005

Antiangiogenic activity of 11,11'-dideoxyverticillin, a natural product isolated from the fungus Shiraia bambusicola.

The fungus Shiraia bambusicola yields the phytochemical 11,11'-dideoxyverticillin, which has been shown to possess potent anticancer activity both in vitro and in vivo. In this study, we reveal that 11,11'-dideoxyverticillin has anti-angiogenic activities and explore the potential mechanisms for this effect. Treatment with 11,11'-dideoxyverticillin inhibited the proliferation of human umbilical vein endothelial cells (HUVECs) with IC(50) values of 0.17+/-0.05muM for VEGF-stimulated cells and 0.39+/-0.08muM for serum-stimulated cells. 11,11'-Dideoxyverticillin also antagonized the antiapoptotic effects of VEGF on serum-deprived HUVECs, inhibited VEGF-induced HUVEC migration in vitro, and blocked serum-induced HUVEC tube formation. Moreover, 11,11'-dideoxyverticillin completely blocked VEGF-induced microvessel sprouting from Matrigel-embedded rat aortic rings and vessel growth in Matrigel plugs in mice. In addition, 11,11'-dideoxyverticillin decreased VEGF secretion by MDA-MB-468 breast cancer cells, and significantly suppressed VEGF-induced tyrosine phosphorylation of Flt-1 and KDR/Flk-1. This inhibition of receptor phosphorylation was correlated with a marked decrease in VEGF-triggered pERK activation and a dramatic increase in pP38 MAPK, but no apparent change in pAkt. Together, these findings strongly suggest that 11,11'-dideoxyverticillin is a structurally novel angiogenesis inhibitor.

Angiogenesis Inhibitors↗
PubMed2005

Free fatty acids administered into the colon promote the secretion of glucagon-like peptide-1 and insulin.

We examined whether free fatty acids (FFAs) promote glucagon-like peptide-1 (GLP-1) secretion when administered into the intestinal tract. We found that an unsaturated long-chain FFA, alpha-linolenic acid (alpha-LA), resulted in increased plasma GLP-1 and insulin levels when administered into the colon. Such stimulatory effects were not apparent with either vehicle or a saturated middle-chain FFA, octanoic acid (OA). Concomitant with GLP-1 secretion, the administration of alpha-LA, but not vehicle or OA, also resulted in a significant increase in the population of pERK positive cells within the GLP-1 positive cells of the colonic mucosa. Moreover, colonic administration of alpha-LA into normal C3H/He mice caused a reduction in plasma glucose levels, as well as in type 2 diabetic model NSY mice. Our results indicate that the in vivo colonic administration of alpha-LA promotes secretion of incretin GLP-1 by activating the ERK pathway in L-cells and thereby enhances the secretion of insulin.

Animals↗
PubMed2006

Ebp1 is a dsRNA-binding protein associated with ribosomes that modulates eIF2alpha phosphorylation.

dsRNA-binding domains (dsRBDs) characterize an expanding family of proteins involved in different cellular processes, ranging from RNA editing and processing to translational control. Here we present evidence that Ebp1, a cell growth regulating protein that is part of ribonucleoprotein (RNP) complexes, contains a dsRBD and that this domain mediates its interaction with dsRNA. Deletion of Ebp1's dsRBD impairs its localization to the nucleolus and its ability to form RNP complexes. We show that in the cytoplasm, Ebp1 is associated with mature ribosomes and that it is able to inhibit the phosphorylation of serine 51 in the eukaryotic initiation factor 2 alpha (eIF2alpha). In response to various cellular stress, eIF2alpha is phosphorylated by distinct protein kinases (PKR, PERK, GCN2, and HRI), and this event results in protein translation shut-down. Ebp1 overexpression in HeLa cells is able to protect eIF2alpha from phosphorylation at steady state and also in response to various treatments. We demonstrate that Ebp1 interacts with and is phosphorylated by the PKR protein kinase. Our results demonstrate that Ebp1 is a new dsRNA-binding protein that acts as a cellular inhibitor of eIF2alpha phosphorylation suggesting that it could be involved in protein translation control.

Adaptor Proteins, Signal Transducing↗
PubMed2005

Serum thymic factor, FTS, attenuates cisplatin nephrotoxicity by suppressing cisplatin-induced ERK activation.

Serum thymic factor (FTS), a thymic peptide hormone, has been reported to attenuate the bleomycin-induced pulmonary injury and also experimental pancreatitis and diabetes. In the present study, we investigated the effect of FTS on cis-diamminedichloroplatinum II (cisplatin)-induced nephrotoxicity. We have already demonstrated that cephaloridine, a nephrotoxic antibiotic, leads to extracellular signal-regulated protein kinase (ERK) activation in the rat kidney, which probably contributes to cephaloridine-induced renal dysfunction. The aim of this study was to examine the effect of cisplatin on ERK activation in the rat kidney and also the effect of FTS on cisplatin-induced nephrotoxicity in rats. In vitro treatment of LLC-PK1 cells with FTS significantly ameliorated cisplatin-induced cell injury. Treatment of rats with intravenous cisplatin for 3 days markedly induced renal dysfunction and increased platinum contents in the kidney cortex. An increase in pERK was detected in the nuclear fraction prepared from the rat kidney cortex from days 1 to 3 after injection of cisplatin. FTS suppressed cisplatin-induced renal dysfunction and ERK activation in the kidney. FTS did not influence any Pt contents in the kidney after cisplatin administration. FTS has been shown to enhance the in vivo expression of heat shock protein (HSP) 70 in the kidney cortex. The beneficial role of FTS against cisplatin nephrotoxicity may be mediated in part by HSP70, as suggested by its up-regulation in the kidney cortex treated with FTS alone. Our results suggest that FTS participates in protection from cisplatin-induced nephrotoxicity by suppressing ERK activation caused by cisplatin.

Animals↗
PubMed2003

Impairments of ERK signal transduction in the brain in a rat model of depression induced by neonatal exposure of clomipramine.

Depression is associated with deficiencies in monoaminergic transmitters and possibly neurotrophins. A common cellular response to these molecules is the activation of extracellular signal-regulated kinase (ERK). A deficiency of ERK signal transduction in depression was therefore hypothesized and was tested in a rat model of depression, produced by neonatal treatment with clomipramine (CLI). We measured sexual behaviors and brain levels of ERK, phosphorylated ERK (pERK), protein phosphatase 1 (PP1), and MAPK phosphatase-2 (MKP-2) during adulthood in control and neonatally CLI-treated rats (CLI rats). As expected, the CLI rats exhibited significantly lower sexual activities and also exhibited (1). significant decreases of pERK1/2 in the frontal cortex and pERK1 in the hippocampus, (2). slight but significant reduction of ERK2 in the frontal cortex and hippocampus, (3). no change of pERK1/2 levels in the temporal cortex, occipital cortex, parietal cortex, midbrain, and medulla, (4). significantly higher levels of PP1 in both the frontal cortex and hippocampus, (5). no change in MKP-2 in any examined region, and (6). all five measures of sexual function were significantly correlated with ERK2 and pERK2 in the frontal cortex. These findings suggest that a deficiency in the ERK signaling pathway is involved in the display of depressive behaviors.

Animals↗
PubMed2006

Down-regulation of IGF-IR using small, interfering, hairpin RNA (siRNA) inhibits growth of human lung cancer cell line A549 in vitro and in nude mice.

Type I insulin-like growth factor receptor (IGF-IR), which is frequently overexpressed in a variety of human cancers including lung cancer, mediates cancer cell proliferation and tumor growth. In this study, we used a human U6 promoter-driven DNA-template approach to induce hairpin RNA (hpRNA)-triggered RNAi to silence IGF-IR gene expression in the human lung cancer cell line A549, and then evaluate its effects on apoptosis, apoptosis-related gene expression, and the growth of tumor cells in vitro and in nude mice. IGF-IR expression levels were found to markedly decrease in cells transfected with a plasmid expressing hairpin siRNA for IGF-IR (by more than 78.9%). Down-regulation of IGR-IR concomitantly accompanied reduction of bcl-2 as well as pERK and pAkt levels, activation of caspase-3, apoptosis and growth inhibition of A549 cells in vitro. Direct intratumoral injections of plasmid DNA expressing hpRNA for IGF-IR significantly regressed pre-established tumors in nude mice. Our results support the therapeutic potential of RNAi as a method for gene therapy in treating lung cancer.

Animals↗
PubMed2006

Hypoxia-induced remodelling of PDE4 isoform expression and cAMP handling in human pulmonary artery smooth muscle cells.

Human pulmonary artery smooth muscle cells (hPASM cells) express PDE4A10, PDE4A11, PDE4B2, PDE4C and PDE4D5 isoforms. Hypoxia causes a transient up-regulation of PDE4B2 that reaches a maximum after 7 days and sustained up-regulation of PDE4A10/11 and PDE4D5 over 14 days in hypoxia. Seven days in hypoxia increases both intracellular cAMP levels, protein kinase A (PKA) activity and activated, phosphorylated extracellular signal regulated kinase (pERK) but does not alter either PKA isoform expression or total cAMP phosphodiesterase-4 (PDE4) activity or cAMP phosphodiesterase-3 (PDE3) activity. Both the cyclooxygenase inhibitor, indomethacin and the ERK inhibitors, UO126 and PD980589 reverse the hypoxia-induced increase in intracellular cAMP levels back to those seen in normoxic hPASM cells. Challenge of normoxic hPASM cells with prostaglandin E(2) (PGE(2)) elevates cAMP to levels comparable to those seen in hypoxic cells but fails to increase intracellular cAMP levels in hypoxic hPASM cells. The adenylyl cyclase activator, forskolin increases cAMP levels in both normoxic and hypoxic hPASM cells to comparable elevated levels. Challenge of hypoxic hPASM cells with indomethacin attenuates total PDE4 activity whilst challenge with UO126 increases total PDE4 activity. We propose that the hypoxia-induced activation of ERK initiates a phospholipase A(2)/COX-driven autocrine effect whereupon PGE(2) is generated, causing the activation of adenylyl cyclase and increase in intracellular cAMP. Despite the hypoxia-induced increases in the expression of PDE4A10/11, PDE4B2 and PDE4D5 and activation of certain of these long PDE4 isoforms through PKA phosphorylation, we suggest that the failure to see any overall increase in PDE4 activity is due to ERK-mediated phosphorylation and inhibition of particular PDE4 long isoforms. Such hypoxia-induced increase in expression of PDE4 isoforms known to interact with certain signalling scaffold proteins may result in alterations in compartmentalised cAMP signalling. The hypoxia-induced increase in cAMP may represent a compensatory protective mechanism against hypoxia-induced mitogens such as endothelin-1 and serotonin.

3',5'-Cyclic-AMP Phosphodiesterases↗
PubMed2005

Induction of human leukemia HL-60 cell differentiation via a PKC/ERK pathway by helenalin, a pseudoguainolide sesquiterpene lactone.

Helenalin, a cell-permeable pseudoguainolide sesquiterpene lactone, is a potent anti-inflammatory agent that inhibits nuclear factor-kappa B (NF-kappa B) DNA binding activity. In this report, we investigated the effect of helenalin on cellular differentiation in the human promyelocytic leukemia HL-60 cell culture system. Helenalin by itself markedly induced HL-60 cell differentiation in a concentration-dependent manner. Cytofluorometric analysis and cell morphologic studies indicated that helenalin induced cell differentiation predominantly into granulocytes. Protein kinase C (PKC) and extracellular signal-regulated kinase (ERK) inhibitors significantly inhibited HL-60 cell differentiation induced by helenalin, while p38 mitogen-activated protein kinase (MAPK) inhibitors did not. Moreover, helenalin enhanced PKC activity and protein level of PKC beta I and PKC beta II isoforms, and also increased the level of pERK in a concentration-dependent manner. In addition, the enhanced levels of cell differentiation closely correlated with the decreased levels of NF-kappa B binding activity by helenalin. These results indicate that PKC, ERK, and NF-kappa B may be involved in HL-60 cell differentiation induced by helenalin.

1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine↗
PubMed2005

Blood-derived macrophages infiltrate the retina and activate Muller glial cells under experimental choroidal neovascularization.

Inflammation is a major mechanism in the pathogenesis of age-related macular degeneration, the most important cause of blindness in the elderly. Previous studies have focused on the role of macrophages in regulating the growth of pathological new vessels over the retina, called choroidal neovascularization (CNV). However, no research has been done to evaluate the role of inflammation as a mechanism of vision loss and retinal degeneration in the retina underlying CNV. In other neuropathological conditions, hematogenous macrophages and/or resident microglia contribute to neurodegeneration. We have combined laser-induced CNV in mice and bone marrow transplantation with GFP-labeled bone marrow to determine the relative role of recruited blood-derived macrophages versus resident microglia in the retina associated with CNV. Using these chimeric mice, we have found that many GFP-labeled cells infiltrated the retina underlying CNV but not the retina unaffected by CNV. Immunostaining for the cell adhesion molecules VCAM 1, ICAM 1, and PECAM was strongly upregulated in retinal blood vessels under CNV. All GFP-labeled cells were immunoreactive for the macrophage marker F4/80. Most (70%) of the F4/80 immunoreactive cells were GFP-labeled under CNV. The density of resident microglia did not increase. Most GFP-labeled cells were found in close proximity to activated Muller cells. Depleting circulating macrophages with clodronic acid diminished the density of F4/80 immunoreactive cells as well as the density of pERK immunoreactive Muller cells in the retina under CNV. Thus, recruitment of blood-derived macrophages more than resident microglia seems to be associated with CNV.

Animals↗
PubMed2006

Constitutive phosphorylation of the S6 ribosomal protein via mTOR and ERK signaling in the peripheral blasts of acute leukemia patients.

OBJECTIVE: The phosphorylation state of the S6 ribosomal protein was measured in the peripheral blasts of 19 newly diagnosed patients with acute leukemia. METHODS: We employed a flow cytometry protocol that enabled correlated measurement of pS6, phosphorylation of extracellular signal-regulated kinase (pERK), and cluster differentiation surface markers. Baseline levels of pS6 in leukemic blasts were compared with those found when the samples were activated using stem cell factor, or exposed to rapamycin, LY294002, or the mitogen-activated protein kinase inhibitor U0126. RESULTS: Results showed a considerable degree of intra- and intertumoral heterogeneity in the constitutive levels of pS6. Rapamycin and LY294002 suppressed pS6 in 10 of 11 cases that showed increased basal levels, consistent with phosphatidylinositol 3 (PI3)-kinase/Akt/mTOR signaling being the predominant upstream signaling pathway. However, in 6 of 11 cases pS6 was also suppressed by U0126, indicating that the ERK pathway can significantly input to pS6. CONCLUSIONS: The constitutive activation of pS6 in acute leukemia patients likely reflects alterations in growth factor signaling that can be mediated by the ERK as well as the mTOR pathway, and could potentially have prognostic significance. As well as identifying aberrant signal transduction in leukemia patients, the flow cytometry methodology has potential for the pharmacodynamic monitoring of novel agents that inhibit ERK or PI3-kinase/Akt/mTOR signaling.

Acute Disease↗
PubMed2006

Increases in the activated forms of ERK 1/2, p38 MAPK, and CREB are correlated with the expression of at-level mechanical allodynia following spinal cord injury.

Rats given moderate spinal cord injury (SCI) display increases in the expression of the activated form of the transcription factor cyclic AMP responsive element binding protein (CREB) in spinal segments of dermatomes corresponding to permanent mechanical allodynia, a model of chronic central neuropathic pain (CNP; (Crown, E.D., Ye, Z., Johnson, K.M., Xu, G.Y., McAdoo, D.J., Westlund, K.N., Hulsebosch, C.E., 2005. Upregulation of the phosphorylated form of CREB in spinothalamic tract cells following spinal cord injury: relation to central neuropathic pain. Neurosci. Lett. 384, 139-144)). Given that not all rats that receive moderate SCI develop CNP, the current study was designed to further analyze changes in persistent CREB activation and in the activation state of upstream intracellular signaling cascades (e.g., mitogen-activated protein kinases [MAPKs]) in populations of rats that receive SCI and weeks later develop CNP and rats that receive SCI but do not develop CNP. The results indicate that activated kinases such as pERK 1/2, p-p38 MAPK, but not pJNK, are upregulated in injured rats that develop CNP as compared to injured rats that fail to develop CNP. In addition, the current results replicated our previous finding that activated CREB is upregulated following SCI, however, only in SCI rats that developed CNP. Taken together, these results indicate that activation of intracellular signaling cascades traditionally associated with long-term potentiation and memory is associated with the expression of chronic CNP following SCI.

Animals↗
PubMed2005

The Pyst2-L phosphatase is involved in cell-crowding.

The dual-specificity phosphatase Pyst2-L was found to be over expressed in leukocytes derived from AML and ALL patients as well as in certain other solid tumors and lymphoblastoid cell lines. Pyst2-L, binds and dephosphorylates both pERKs and pJNKs proteins, and thus, plays a role in regulating the MAP kinase signaling pathway. In the present study, a comparative genomic application was used and sequence analysis of multi-organisms databases were searched in order to identify genes homologous to Pyst2-L. The Xenopus laevis MAP kinase phosphatase X17c gene and the Yeast nitrogen starvation-induced protein phosphatase Yvh1p gene were revealed to be highly homologous with Pyst2-L. Both X17c and Yvh1p genes play a role in cell cycle regulation. A down regulated expression of the Yvh1p gene occurred in Saccharomyces cerevisiae that were synchronized to the G2-phase of the cell cycle by alpha-factor. In conformity with this result, a reduction in Pyst2-L expression levels was observed in G2-phase-synchronized Human K562 cells. Finally, we were able to show that cells in highly crowded cultures express high levels of the Pyst2-L phosphatase. These observations may indicate that low levels of the Pyst2-L phosphatase are essential for the G2-phase of the cell cycle and that this phosphatase might play a role in signaling cascades induced by cellular crowding.

Amino Acid Sequence↗
PubMed2005

Principles of fracture remodeling in children.

In treating fractures in children, the surgeon must have a good knowledge of the three phases of bone healing, ie, inflammatory, reparative, and remodeling and understand how they contribute to the final recovery of the fracture healing process. By and large, the ability to remodel depends on the bone involved, the patient's age, the proximity to the joint, and its orientation to the joint axis. In the typical long bone, 75% of the remodeling occurs by reorientation of the physis while appositional remodeling of the diaphysis can only be expected to contribute 25% to the remodeling process. The various values of acceptable alignment for each of the major fracture patterns are outlined. These serve only as guidelines. The patient's functional capacity and the surgeon's experience should also be factors in determining whether to depend on the remodeling capacity of the specific fracture or to consider performing a more aggressive, invasive technique to achieve a satisfactory result. There are two advantages in treating children's fractures. First, the healing process is very rapid. Nonunion is a rare event in the pediatric age group. The second perk is that there is a very good remodeling capacity should there be less than anatomical alignment of the affected bone once the fracture has healed. Any individual treating fractures in the pediatric age group should fully understand how pediatric fractures heal and how the remodeling process occurs.

Arm Injuries↗
PubMed2004

Induction of neuronal death by ER stress in Alzheimer's disease.

Recent studies have suggested that neuronal death in Alzheimer's disease (AD) or ischemia could arise from dysfunction of the endoplasmic reticulum (ER). Inhibition of protein glycosylation, perturbation of calcium homeostasis, and reduction of disulfide bonds provoke accumulation of unfolded protein in the ER, and are called 'ER stress'. Normal cells respond to ER stress by increasing transcription of genes encoding ER-resident chaperones such as GRP78/BiP, to facilitate protein folding or by suppressing the mRNA translation to synthesize proteins. These systems are termed the unfolded protein response (UPR). Familial Alzheimer's disease-linked presenilin-1 (PS1) mutation downregulates the unfolded protein response and leads to vulnerability to ER stress. The mechanisms by which mutant PS1 affects the ER stress response are attributed to the inhibited activation of ER stress transducers such as IRE1, PERK and ATF6. On the other hand, in sporadic Alzheimer's disease (sAD), we found the aberrant splicing isoform (PS2V), generated by exon 5 skipping of the Presenilin-2 (PS2) gene transcript, responsible for induction of high mobility group A1a protein (HMGA1a). The PS2V also downregulates the signaling pathway of the UPR, in a similar fashion to that reported for mutants of PS1 linked to familial AD. It was clarified what molecules related to cell death are activated in the case of AD and we discovered that caspase-4 plays a key role in ER stress-induced apoptosis. Caspase-4 also seems to act upstream of the beta-amyloid-induced ER stress pathway, suggesting that activation of caspase-4 might mediate neuronal cell death in AD.

Alzheimer Disease↗
PubMed2005

Epidermal growth factor receptor, HER-2/neu and related pathways in lung adenocarcinomas with bronchioloalveolar features.

Lung adenocarcinomas with bronchioalveolar features (ABAF), formerly called bronchioloalveolar cancers (BAC), constitute a distinct clinical, radiological and pathological entity among lung malignancies. Epidermal growth factor receptor (EGFR) and to a less extent, HER-2/neu, are known to be overexpressed in non-small lung cancers, but their exact status in ABAF is not well-documented. Stimulation of these two receptors results in the initiation of two major cascades, namely phosphatidylinositol 3-kinase (PI-3K) and Ras-dependent pathways. We have therefore studied the expressions of EGFR, HER-2/neu as well as phosphorylated AKT (pAKT) and phosphorylated extracellular-signal regulated kinase (ERK), which are key molecules in these two pathways, in 15 ABAF patients. EGFR was found to be overexpressed in 9 of 15 patients (60%). HER-2/neu overexpression was detected in 6 of the 14 tumors tested (43%). pAKT and pERK were both found to be positive in 13 of 15 patients (87%). Six of the seven tumors with mucinous pattern were negative for EGFR, while all of the other eight cases were positive (P=0.001). Mucinous tumors were also less likely than non-mucinous tumors to overexpress HER-2/neu (17% versus 63%, respectively). These findings suggest that ABAF, particularly those with non-mucinous histology, commonly harbors EGFR and HER-2/neu overexpression. PI-3K and Ras-dependant pathways that lie downstream are generally activated, even in the absence of EGFR and/or HER-2/neu overexpression. ABAF may be a particularly promising candidate for EGFR-targeted strategies and this possibility merits extensive evaluation in clinical trials.

Adenocarcinoma, Bronchiolo-Alveolar↗
PubMed2006

Adenovirus expressing shRNA to IGF-1R enhances the chemosensitivity of lung cancer cell lines by blocking IGF-1 pathway.

RNA interference is a phenomenon whereby small double-stranded RNA knocks down the expression of a sequence-specific gene. Double-stranded siRNA transfection, as currently used, is considered to have transient and low transfection efficiency. We constructed an adenoviral vector-based short hair-pin(sh)RNA system to overcome the limitations of the genetic blockade of IGF-1R, one of most important cancer therapy targets. We constructed three different IGF-1R specific shRNAs (612, 801, and 3425) and generated three ad-shIGF-1Rs using BD Adeno-X expression system. We assessed the effect of ad-shIGF-1R on signal transduction, induction of apoptosis, and in vitro tumorigenicity of lung cancer cell lines. Western blot and FACS assays demonstrated that endogenous IGF-1R expression was efficiently suppressed after transduction of lung cancer cell lines with the three different ad-shIGF-1Rs. IGF-1R blockade by ad-shIGF-1R inhibited ligand induced phosphorylation of pAkt and pErk, and ad-shIGF-1R effectively blocked the in vitro tumorigenicity of lung cancer cell lines. Moreover, the transduction of a human lung cancer cell line with ad-IGF-1R(3425) enhanced chemosensitivity to anticancer drugs. We conclude that the adenoviral vector-based approach to the RNA interference of IGF-1R induced effective IGF-1R silencing in lung cancer cell lines as manifested by effective blocking of the downstream pathway of IGF-1R and by an antitumor effect. We believe that this system can be usefully applied to other cancer targets.

Adenoviridae↗