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Samuel A. Mantey - One of the best experts on this subject based on the ideXlab platform.
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bombesin receptor subtype 3 agonists stimulate the growth of lung cancer cells and increase egf receptor tyrosine phosphorylation
Peptides, 2011Co-Authors: Terry W. Moody, Veronica Sancho, Bernardo Nucheberenguer, Alessia Di Florio, Samuel A. ManteyAbstract:The effects of bombesin receptor subtype-3 (BRS-3) agonists were investigated on lung cancer cells. The BRS-3 agonist (DTyr(6), (Ala(11), Phe(13), Nle(14)) bombesin(6-14) (BA1), but not gastrin releasing peptide (GRP) or neuromedin B (NMB) increased significantly the clonal growth of NCI-H1299 cells stably transfected with BRS-3 (NCI-H1299-BRS-3). Also, BA1 addition to NCI-H727 or NCI-H1299-BRS-3 cells caused Tyr(1068) phosphorylation of the epidermal growth factor receptor (EGFR). Similarly, (DTyr(6), R-Apa(11), Phe(13), Nle(14)) bombesin(6-14) (BA2) and (DTyr(6), R-Apa(11), 4-Cl,Phe(13), Nle(14)) bombesin(6-14) (BA3) but not gastrin releasing peptide (GRP) or neuromedin B (NMB) caused EGFR transactivation in NCI-H1299-BRS-3 cells. BA1-induced EGFR or ERK tyrosine phosphorylation was not inhibited by addition of BW2258U89 (BB(2)R antagonist) or PD168368 (BB(1)R antagonist) but was blocked by (DNal-Cys-Tyr-DTrp-Lys-Val-Cys-Nal)NH(2) (BRS-3 ant.). The BRS-3 ant. reduced clonal growth of NCI-H1299-BRS-3 cells. BA1, BA2, BA3 and BRS-3 ant. inhibit specific (125)I-BA1 binding to NCI-H1299-BRS-3 cells with an IC(50) values of 1.1, 21, 15 and 750nM, respectively. The ability of BRS-3 to regulate EGFR transactivation in NCI-H1299-BRS-3 cells was reduced by AG1478 or gefitinib (EGFR tyrosine kinase inhibitors), GM6001 (matrix metalloprotease inhibitor), PP2 (Src inhibitor), N-acetylcysteine (anti-oxidant), Tiron (superoxide scavenger) and DPI (NADPH oxidase inhibitor). These results demonstrate that BRS-3 agonists may stimulate lung cancer growth as a result of EGFR transactivation and that the transactivation is regulated by BRS-3 in a Src-, reactive oxygen and matrix metalloprotease-dependent manner.
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Neuromedin B receptors regulate EGF receptor tyrosine phosphorylation in lung cancer cells
European Journal of Pharmacology, 2010Co-Authors: Terry W. Moody, Samuel A. Mantey, Marc J. Berna, Veronica Sancho, Lisa A. Ridnour, David A. Wink, Daniel Chan, Giuseppe GiacconeAbstract:Neuromedin B (NMB), a member of the bombesin family of peptides, is an autocrine growth factor for many lung cancer cells. The present study investigated the ability of NMB to cause transactivation of the epidermal growth factor (EGF) receptor in lung cancer cells. By Western blot, addition of NMB or related peptides to NCI-H1299 human non-small cell lung cancer (NSCLC) cells, caused phosphorylation of Tyr1068 of the EGF receptor. The signal was amplified using NCI-H1299 cells stably transected with NMB receptors. The transactivation of the EGF receptor or the tyrosine phosphorylation of ERK caused by NMB-like peptides was inhibited by AG1478 or gefitinib (tyrosine kinase inhibitors) and NMB receptor antagonist PD168368 but not the GRP receptor antagonist, BW2258U89. The transactivation of the EGF receptor caused by NMB-like peptides was inhibited by GM6001 (matrix metalloprotease inhibitor), PP2 (Src inhibitor), or transforming growth factor (TGF)α antibody. The transactivation of the EGF receptor and the increase in reactive oxygen species caused by NMB-like peptides was inhibited by N-acetylcysteine (NAC) or Tiron. Gefitinib inhibited the proliferation of NCI-H1299 cells and its sensitivity was increased by the addition of PD168368. The results indicate that the NMB receptor regulates EGF receptor transactivation by a mechanism dependent on Src as well as metalloprotease activation and generation of reactive oxygen species.
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bombesin marine toxin conjugates inhibit the growth of lung cancer cells
Life Sciences, 2008Co-Authors: Terry W. Moody, Samuel A. Mantey, Tapas K Pradhan, Robert T Jensen, Marcin Dyba, Deborah L Moody, Nadya I Tarasova, Christopher J MichejdaAbstract:Hemiasterlin (Hem) and dolastatin (Dol) are marine natural products which are cytotoxic for cancer cells. Hem, a tripeptide, and Dol, a hexapeptide, were conjugated with linkers (L) to the universal BB agonist DPhe-Gln-Trp-Ala-Val-betaAla-His-Phe-Nle-NH2(BA1) and the effects of the Hem-BB and Dol-BB conjugates investigated on NCI-H1299 lung cancer cells. Hem-LA-BA1 and Hem-LB-BA1 inhibited specific (125I-Tyr4)BB binding to NCI-H1299 cells, which have BB2 receptors (R), with IC50 values of 15 and 25 nM, respectively. Addition of Hem-LA-BA1 and Hem-LB-BA1 to Fura-2 AM loaded cells containing BB2R, caused elevated cytosolic Ca2+. In a growth assay, Hem-LA-BA1 and Hem-LB-BA1 inhibited the proliferation of NCI-H1299 cells. Dol-succinamide (Dols)-LD-BA1 and Dols-LE-BA1 bound with high affinity to NCI-H1299 cells and elevated cytosolic Ca2+, but did not inhibit the proliferation of NCI-H1299 cells. Also, Hem-LA-BA1 inhibited 125I-DTyr-Gln-Trp-Ala-Val-betaAla-His-Phe-Nle-NH2 (BA2) binding to Balb/3T3 cells transfected with BB1R or BB2R as well as with BRS-3 with IC50 values of 130, 8, and 540 nM, respectively. These results show that Hem-BB conjugates are cytotoxic for cancer cells containing BB2R.
Terry W. Moody - One of the best experts on this subject based on the ideXlab platform.
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bombesin receptor subtype 3 agonists stimulate the growth of lung cancer cells and increase egf receptor tyrosine phosphorylation
Peptides, 2011Co-Authors: Terry W. Moody, Veronica Sancho, Bernardo Nucheberenguer, Alessia Di Florio, Samuel A. ManteyAbstract:The effects of bombesin receptor subtype-3 (BRS-3) agonists were investigated on lung cancer cells. The BRS-3 agonist (DTyr(6), (Ala(11), Phe(13), Nle(14)) bombesin(6-14) (BA1), but not gastrin releasing peptide (GRP) or neuromedin B (NMB) increased significantly the clonal growth of NCI-H1299 cells stably transfected with BRS-3 (NCI-H1299-BRS-3). Also, BA1 addition to NCI-H727 or NCI-H1299-BRS-3 cells caused Tyr(1068) phosphorylation of the epidermal growth factor receptor (EGFR). Similarly, (DTyr(6), R-Apa(11), Phe(13), Nle(14)) bombesin(6-14) (BA2) and (DTyr(6), R-Apa(11), 4-Cl,Phe(13), Nle(14)) bombesin(6-14) (BA3) but not gastrin releasing peptide (GRP) or neuromedin B (NMB) caused EGFR transactivation in NCI-H1299-BRS-3 cells. BA1-induced EGFR or ERK tyrosine phosphorylation was not inhibited by addition of BW2258U89 (BB(2)R antagonist) or PD168368 (BB(1)R antagonist) but was blocked by (DNal-Cys-Tyr-DTrp-Lys-Val-Cys-Nal)NH(2) (BRS-3 ant.). The BRS-3 ant. reduced clonal growth of NCI-H1299-BRS-3 cells. BA1, BA2, BA3 and BRS-3 ant. inhibit specific (125)I-BA1 binding to NCI-H1299-BRS-3 cells with an IC(50) values of 1.1, 21, 15 and 750nM, respectively. The ability of BRS-3 to regulate EGFR transactivation in NCI-H1299-BRS-3 cells was reduced by AG1478 or gefitinib (EGFR tyrosine kinase inhibitors), GM6001 (matrix metalloprotease inhibitor), PP2 (Src inhibitor), N-acetylcysteine (anti-oxidant), Tiron (superoxide scavenger) and DPI (NADPH oxidase inhibitor). These results demonstrate that BRS-3 agonists may stimulate lung cancer growth as a result of EGFR transactivation and that the transactivation is regulated by BRS-3 in a Src-, reactive oxygen and matrix metalloprotease-dependent manner.
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Neuromedin B receptors regulate EGF receptor tyrosine phosphorylation in lung cancer cells
European Journal of Pharmacology, 2010Co-Authors: Terry W. Moody, Samuel A. Mantey, Marc J. Berna, Veronica Sancho, Lisa A. Ridnour, David A. Wink, Daniel Chan, Giuseppe GiacconeAbstract:Neuromedin B (NMB), a member of the bombesin family of peptides, is an autocrine growth factor for many lung cancer cells. The present study investigated the ability of NMB to cause transactivation of the epidermal growth factor (EGF) receptor in lung cancer cells. By Western blot, addition of NMB or related peptides to NCI-H1299 human non-small cell lung cancer (NSCLC) cells, caused phosphorylation of Tyr1068 of the EGF receptor. The signal was amplified using NCI-H1299 cells stably transected with NMB receptors. The transactivation of the EGF receptor or the tyrosine phosphorylation of ERK caused by NMB-like peptides was inhibited by AG1478 or gefitinib (tyrosine kinase inhibitors) and NMB receptor antagonist PD168368 but not the GRP receptor antagonist, BW2258U89. The transactivation of the EGF receptor caused by NMB-like peptides was inhibited by GM6001 (matrix metalloprotease inhibitor), PP2 (Src inhibitor), or transforming growth factor (TGF)α antibody. The transactivation of the EGF receptor and the increase in reactive oxygen species caused by NMB-like peptides was inhibited by N-acetylcysteine (NAC) or Tiron. Gefitinib inhibited the proliferation of NCI-H1299 cells and its sensitivity was increased by the addition of PD168368. The results indicate that the NMB receptor regulates EGF receptor transactivation by a mechanism dependent on Src as well as metalloprotease activation and generation of reactive oxygen species.
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bombesin marine toxin conjugates inhibit the growth of lung cancer cells
Life Sciences, 2008Co-Authors: Terry W. Moody, Samuel A. Mantey, Tapas K Pradhan, Robert T Jensen, Marcin Dyba, Deborah L Moody, Nadya I Tarasova, Christopher J MichejdaAbstract:Hemiasterlin (Hem) and dolastatin (Dol) are marine natural products which are cytotoxic for cancer cells. Hem, a tripeptide, and Dol, a hexapeptide, were conjugated with linkers (L) to the universal BB agonist DPhe-Gln-Trp-Ala-Val-betaAla-His-Phe-Nle-NH2(BA1) and the effects of the Hem-BB and Dol-BB conjugates investigated on NCI-H1299 lung cancer cells. Hem-LA-BA1 and Hem-LB-BA1 inhibited specific (125I-Tyr4)BB binding to NCI-H1299 cells, which have BB2 receptors (R), with IC50 values of 15 and 25 nM, respectively. Addition of Hem-LA-BA1 and Hem-LB-BA1 to Fura-2 AM loaded cells containing BB2R, caused elevated cytosolic Ca2+. In a growth assay, Hem-LA-BA1 and Hem-LB-BA1 inhibited the proliferation of NCI-H1299 cells. Dol-succinamide (Dols)-LD-BA1 and Dols-LE-BA1 bound with high affinity to NCI-H1299 cells and elevated cytosolic Ca2+, but did not inhibit the proliferation of NCI-H1299 cells. Also, Hem-LA-BA1 inhibited 125I-DTyr-Gln-Trp-Ala-Val-betaAla-His-Phe-Nle-NH2 (BA2) binding to Balb/3T3 cells transfected with BB1R or BB2R as well as with BRS-3 with IC50 values of 130, 8, and 540 nM, respectively. These results show that Hem-BB conjugates are cytotoxic for cancer cells containing BB2R.
Chung S Yang - One of the best experts on this subject based on the ideXlab platform.
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epigallocatechin gallate suppresses lung cancer cell growth through ras gtpase activating protein sh3 domain binding protein 1
Cancer Prevention Research, 2010Co-Authors: Junghyun Shim, Ann M Bode, Zhengyuan Su, Jungil Chae, Chung S Yang, Zigang DongAbstract:Green tea is a highly popular beverage globally. Green tea contains a number of polyphenol compounds referred to as catechins, and (−)-epigallocatechin gallate (EGCG) is believed to be the major biologically active compound found in green tea. EGCG has been reported to suppress lung cancer, but the molecular mechanisms of the inhibitory effects of EGCG are not clear. We found that EGCG interacted with the Ras–GTPase-activating protein SH3 domain-binding protein 1 (G3BP1) with high binding affinity ( K d = 0.4 μmol/L). We also showed that EGCG suppressed anchorage-independent growth of H1299 and CL13 lung cancer cells, which contain an abundance of the G3BP1 protein. EGCG was much less effective in suppressing anchorage-independent growth of H460 lung cancer cells, which express much lower levels of G3BP1. Knockdown shG3BP1-transfected H1299 cells exhibited substantially decreased proliferation and anchorage-independent growth. shG3BP1 H1299 cells were resistant to the inhibitory effects of EGCG on growth and colony formation compared with shMock-transfected H1299 cells. EGCG interfered with the interaction of G3BP1 and the Ras–GTPase-activating protein and further suppressed the activation of Ras. Additional results revealed that EGCG effectively attenuated G3BP1 downstream signaling, including extracellular signal-regulated kinase and mitogen-activated protein kinase/extracellular signal-regulated kinase kinase, in wild-type H1299 and shMock H1299 cells but had little effect on H460 or shG3BP1 H1299 cells. Overall, these results strongly indicate that EGCG suppresses lung tumorigenesis through its binding with G3BP1. Cancer Prev Res; 3(5); 670–9. ©2010 AACR.
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monodemethylated polymethoxyflavones from sweet orange citrus sinensis peel inhibit growth of human lung cancer cells by apoptosis
Molecular Nutrition & Food Research, 2009Co-Authors: Hang Xiao, Chung S Yang, Huanyu Jin, Trusha PatelAbstract:Polymethoxyflavones (PMFs) are almost exclusively found in the Citrus genus, particularly in the peels of sweet orange (Citrus sinensis L. Osbeck) and mandarin (C. reticulate Blanco). We studied the effects of two major PMFs, namely, nobiletin and 3,5,6,7,8,3',4'-heptamethoxyflavone (HMF), and two major monodemethylated PMFs, namely 5-hydroxy-3,7,8,3',4'-pentamethoxyflavone (5HPMF), and 5-hydroxy-3,6,7,8,3',4'-hexamethoxyflavone (5HHMF), on the growth of human lung cancer H1299, H441, and H460 cells. Monodemethylated PMFs were much more potent in growth inhibition of lung cancer cells than their permethoxylated counterpart PMFs. In H1299 cells, cell cycle analyses further revealed that monodemethylated PMFs caused significant increase in sub-G0/G1 phase, suggesting possible role of apoptosis in the growth inhibition observed, whereas the permethoxylated counterpart PMFs did not affect cell cycle distribution at same concentrations tested. These results strongly suggested that the phenolic group is essential for the growth inhibitory activity of monodemethylated PMFs. Further studies in H1299 cells demonstrated that monodemethylated PMFs downregulated oncogenic proteins, such as iNOS, COX-2, Mcl-1, and K-ras, as well as induced apoptosis evidenced by activation of caspase-3 and cleavage of PARP. Our results provide rationale to develop orange peel extract enriched with monodemethylated PMFs into value-added nutraceutical products for cancer prevention.
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green tea polyphenol epigallocatechin 3 gallate induces oxidative stress and dna damage in cancer cell lines xenograft tumors and mouse liver
Cancer Research, 2006Co-Authors: Hang Xiao, Joshua D Lambert, Chung S YangAbstract:Proc Amer Assoc Cancer Res, Volume 47, 2006 4896 (-)-Epigallocatechin-3-gallate (EGCG), the major polyphenol in green tea, has been shown to inhibit cancer cell growth and tumorigenesis in animal models. Our previous work has shown that the auto-oxidation of EGCG in the culture medium caused apoptosis and inactivation of growth factor receptors. In the present studies with superoxide dismutase (SOD) and catalase in the medium to stabilize EGCG, EGCG (20 or 50 μM) could still induce intracellular ROS in both esophageal squamous cell carcinoma KYSE 150 and non-small cell lung cancer H1299 cells determined by dichlorofluorescin staining. These signals can be greatly reduced by the presence of N -acetyl-cysteine, which can penetrate the cell membrane and reach the cytosol. As a consequence of ROS induction, 15 μM EGCG increased the level of phospho-H2A.X, a DNA double strand break marker, in H1299 cells in the presence of SOD and catalase after 48 h of incubation. This treatment also caused 50% inhibition on H1299 cell growth and 25% cells in early apoptotic state. This suggests that EGCG-induced ROS could damage DNA and possibly contribute to the growth inhibition effect. Utilizing the tissue and tumor samples from an H1299 xenograft study, we observed that EGCG administration to NCR nu/nu mice could induce the up-regulation of oxidative stress and DNA damage markers. In the mouse liver, i.p. injection of 40 or 80 mg/kg EGCG daily for 4 weeks led to the increase of phospho-H2A.X and metallothionein expression, suggesting the presence of oxidative stress. EGCG administration through diet (0.2%) or in drinking fluid (0.32%) did not have such effects. The growth of H1299 xenograft tumors was inhibited by 50% as a result of i.p. injection of 40 mg/kg EGCG daily for 4 weeks. Phospho-H2A.X level was significantly increased in tumors of the treatment group compared to those of control. EGCG is generally considered to be an antioxidant. More studies are needed to determine whether the pro-oxidative activities of EGCG can contribute to tumor growth inhibition and oxidative stress to the host animals (supported by NIH grants CA 88961 and CA 56673).
Hang Xiao - One of the best experts on this subject based on the ideXlab platform.
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monodemethylated polymethoxyflavones from sweet orange citrus sinensis peel inhibit growth of human lung cancer cells by apoptosis
Molecular Nutrition & Food Research, 2009Co-Authors: Hang Xiao, Chung S Yang, Huanyu Jin, Trusha PatelAbstract:Polymethoxyflavones (PMFs) are almost exclusively found in the Citrus genus, particularly in the peels of sweet orange (Citrus sinensis L. Osbeck) and mandarin (C. reticulate Blanco). We studied the effects of two major PMFs, namely, nobiletin and 3,5,6,7,8,3',4'-heptamethoxyflavone (HMF), and two major monodemethylated PMFs, namely 5-hydroxy-3,7,8,3',4'-pentamethoxyflavone (5HPMF), and 5-hydroxy-3,6,7,8,3',4'-hexamethoxyflavone (5HHMF), on the growth of human lung cancer H1299, H441, and H460 cells. Monodemethylated PMFs were much more potent in growth inhibition of lung cancer cells than their permethoxylated counterpart PMFs. In H1299 cells, cell cycle analyses further revealed that monodemethylated PMFs caused significant increase in sub-G0/G1 phase, suggesting possible role of apoptosis in the growth inhibition observed, whereas the permethoxylated counterpart PMFs did not affect cell cycle distribution at same concentrations tested. These results strongly suggested that the phenolic group is essential for the growth inhibitory activity of monodemethylated PMFs. Further studies in H1299 cells demonstrated that monodemethylated PMFs downregulated oncogenic proteins, such as iNOS, COX-2, Mcl-1, and K-ras, as well as induced apoptosis evidenced by activation of caspase-3 and cleavage of PARP. Our results provide rationale to develop orange peel extract enriched with monodemethylated PMFs into value-added nutraceutical products for cancer prevention.
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Synergistic effects of a novel combination of polyphenon E and atorvastatin in inhibition of lung tumor
Cancer Epidemiology and Prevention Biomarkers, 2007Co-Authors: Hang Xiao, Hui You, Blake Snagaski, Chung YangAbstract:A115 The present study investigated the synergistic inhibitory effects of polyphenon E (PPE, a standardized green tea polyphenol preparations containing appromately 65% EGCG), and atorvastatin (ATST) in a 4-(methylnitrosaminao)-1-(3-pyridyl)-1-butanone (NNK)-induced lung tumorigenesis model and H1299 human lung cancer cell line. Female A/J mice were given two weekly i.p. injections of NNK (150 mg/kg total dose), and one week later, they were treated with PPE (0.25% or 0.5% in drinking fluid), ATST (200 ppm or 400 ppm in diet), or PPE (0.25%) plus ATST (200ppm) for 16 weeks. With the single agents, only the high doses were effective in inhibiting lung tumorigenesis. However, the combination of PPE/ATST significantly reduced both the tumor multiplicity and tumor burden (by 56% and 55%, respectively). Synergistic reduction of tumor multiplicity (p = 0.0006) and tumor burden (p = 0.0009) by this combination was indicated by the isobologram analysis, which is used for studying the interaction of two agents. This conclusion was further supported by an isobologram analysis of the inhibitory effect of this combination in H1299 human lung cancer cells, where the combination of these two agents synergistically decreased the number of viable cells. >Immunohistochemistry analyses on the lung tumor tissues demonstrated that the combination of low doses PPE and ATST significantly induced apoptosis in tumors (3.2 fold of the control); whereas 0.5% PPE or 400ppm ATST alone increased the apoptotic indexes by 1.8 fold and 1.4 fold respectively. Induction of apoptosis was also found in H1299 cells by the TUNEL assay, and the combination of PPE/ATST was more efficient in enhancing the cleaved-caspase 3, 9, and PRPP levels than the single agent treatment. The induced apoptosis by the combination of PPE/ATST was possibly due to the reduced levels of anti-apoptotic proteins Mcl-1 and Bax. In both the NNK-induced lung tumors and H1299 cells, the Mcl-1 and Bax levels were reduced by PPE/ATST combination by Western blot and immunohistochemistry. The reductions of Mcl-1 and Bax levels by the combination were more significant than PPE or ATST alone. Cyclin D1 and hyper-phosphorylated Rb protein levels were also significantly reduced by this combination in H1299 cells, suggesting the inhibition of cell proliferation. The present work demonstrated that PPE and ATST synergistically inhibited NNK-induced lung tumorigenesis in mice and the growth of lung cancer H1299 cells. This effect is most likely due to the induction of cell apoptosis through inhibition of Mcl-1 (supported by NIH grant CA88961).
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green tea polyphenol epigallocatechin 3 gallate induces oxidative stress and dna damage in cancer cell lines xenograft tumors and mouse liver
Cancer Research, 2006Co-Authors: Hang Xiao, Joshua D Lambert, Chung S YangAbstract:Proc Amer Assoc Cancer Res, Volume 47, 2006 4896 (-)-Epigallocatechin-3-gallate (EGCG), the major polyphenol in green tea, has been shown to inhibit cancer cell growth and tumorigenesis in animal models. Our previous work has shown that the auto-oxidation of EGCG in the culture medium caused apoptosis and inactivation of growth factor receptors. In the present studies with superoxide dismutase (SOD) and catalase in the medium to stabilize EGCG, EGCG (20 or 50 μM) could still induce intracellular ROS in both esophageal squamous cell carcinoma KYSE 150 and non-small cell lung cancer H1299 cells determined by dichlorofluorescin staining. These signals can be greatly reduced by the presence of N -acetyl-cysteine, which can penetrate the cell membrane and reach the cytosol. As a consequence of ROS induction, 15 μM EGCG increased the level of phospho-H2A.X, a DNA double strand break marker, in H1299 cells in the presence of SOD and catalase after 48 h of incubation. This treatment also caused 50% inhibition on H1299 cell growth and 25% cells in early apoptotic state. This suggests that EGCG-induced ROS could damage DNA and possibly contribute to the growth inhibition effect. Utilizing the tissue and tumor samples from an H1299 xenograft study, we observed that EGCG administration to NCR nu/nu mice could induce the up-regulation of oxidative stress and DNA damage markers. In the mouse liver, i.p. injection of 40 or 80 mg/kg EGCG daily for 4 weeks led to the increase of phospho-H2A.X and metallothionein expression, suggesting the presence of oxidative stress. EGCG administration through diet (0.2%) or in drinking fluid (0.32%) did not have such effects. The growth of H1299 xenograft tumors was inhibited by 50% as a result of i.p. injection of 40 mg/kg EGCG daily for 4 weeks. Phospho-H2A.X level was significantly increased in tumors of the treatment group compared to those of control. EGCG is generally considered to be an antioxidant. More studies are needed to determine whether the pro-oxidative activities of EGCG can contribute to tumor growth inhibition and oxidative stress to the host animals (supported by NIH grants CA 88961 and CA 56673).
Veronica Sancho - One of the best experts on this subject based on the ideXlab platform.
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bombesin receptor subtype 3 agonists stimulate the growth of lung cancer cells and increase egf receptor tyrosine phosphorylation
Peptides, 2011Co-Authors: Terry W. Moody, Veronica Sancho, Bernardo Nucheberenguer, Alessia Di Florio, Samuel A. ManteyAbstract:The effects of bombesin receptor subtype-3 (BRS-3) agonists were investigated on lung cancer cells. The BRS-3 agonist (DTyr(6), (Ala(11), Phe(13), Nle(14)) bombesin(6-14) (BA1), but not gastrin releasing peptide (GRP) or neuromedin B (NMB) increased significantly the clonal growth of NCI-H1299 cells stably transfected with BRS-3 (NCI-H1299-BRS-3). Also, BA1 addition to NCI-H727 or NCI-H1299-BRS-3 cells caused Tyr(1068) phosphorylation of the epidermal growth factor receptor (EGFR). Similarly, (DTyr(6), R-Apa(11), Phe(13), Nle(14)) bombesin(6-14) (BA2) and (DTyr(6), R-Apa(11), 4-Cl,Phe(13), Nle(14)) bombesin(6-14) (BA3) but not gastrin releasing peptide (GRP) or neuromedin B (NMB) caused EGFR transactivation in NCI-H1299-BRS-3 cells. BA1-induced EGFR or ERK tyrosine phosphorylation was not inhibited by addition of BW2258U89 (BB(2)R antagonist) or PD168368 (BB(1)R antagonist) but was blocked by (DNal-Cys-Tyr-DTrp-Lys-Val-Cys-Nal)NH(2) (BRS-3 ant.). The BRS-3 ant. reduced clonal growth of NCI-H1299-BRS-3 cells. BA1, BA2, BA3 and BRS-3 ant. inhibit specific (125)I-BA1 binding to NCI-H1299-BRS-3 cells with an IC(50) values of 1.1, 21, 15 and 750nM, respectively. The ability of BRS-3 to regulate EGFR transactivation in NCI-H1299-BRS-3 cells was reduced by AG1478 or gefitinib (EGFR tyrosine kinase inhibitors), GM6001 (matrix metalloprotease inhibitor), PP2 (Src inhibitor), N-acetylcysteine (anti-oxidant), Tiron (superoxide scavenger) and DPI (NADPH oxidase inhibitor). These results demonstrate that BRS-3 agonists may stimulate lung cancer growth as a result of EGFR transactivation and that the transactivation is regulated by BRS-3 in a Src-, reactive oxygen and matrix metalloprotease-dependent manner.
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Bombesin receptor subtype-3 agonists stimulate the growth of lung cancer cells and increase EGF receptor tyrosine phosphorylation
'Elsevier BV', 2011Co-Authors: Moody, Terry W., Veronica Sancho, Di Florio Alessia, Nuche-berenguer Bernardo, Mantey Samuel, Jensen, Robert T.Abstract:The effects of bombesin receptor subtype-3 (BRS-3) agonists were investigated on lung cancer cells. The BRS-3 agonist (DTyr6, (Ala11, Phe13, Nle14) bombesin6-14(BA1), but not gastrin releasing peptide (GRP) or neuromedin B (NMB) increased significantly the clonal growth of NCI-H1299 cells stably transfected with BRS-3 (NCI-H1299-BRS-3). Also, BA1 addition to NCI-H727 or NCI-H1299-BRS-3 cells caused Tyr1068phosphorylation of the epidermal growth factor receptor (EGFR). Similarly, (DTyr6, R-Apa11, Phe13, Nle14) bombesin6-14(BA2) and (DTyr6, R-Apa11, 4-Cl,Phe13, Nle14) bombesin6-14(BA3) but not gastrin releasing peptide (GRP) or neuromedin B (NMB) caused EGFR transactivation in NCI-H1299-BRS-3 cells. BA1-induced EGFR or ERK tyrosine phosphorylation was not inhibited by addition of BW2258U89 (BB2R antagonist) or PD168368 (BB1R antagonist) but was blocked by (DNal-Cys-Tyr-DTrp-Lys-Val-Cys-Nal)NH2(BRS-3 ant.). The BRS-3 ant. reduced clonal growth of NCI-H1299-BRS-3 cells. BA1, BA2, BA3 and BRS-3 ant. inhibit specific125I-BA1 binding to NCI-H1299-BRS-3 cells with an IC50values of 1.1, 21, 15 and 750 nM, respectively. The ability of BRS-3 to regulate EGFR transactivation in NCI-H1299-BRS-3 cells was reduced by AG1478 or gefitinib (EGFR tyrosine kinase inhibitors), GM6001 (matrix metalloprotease inhibitor), PP2 (Src inhibitor), N-acetylcysteine (anti-oxidant), Tiron (superoxide scavenger) and DPI (NADPH oxidase inhibitor). These results demonstrate that BRS-3 agonists may stimulate lung cancer growth as a result of EGFR transactivation and that the transactivation is regulated by BRS-3 in a Src-, reactive oxygen and matrix metalloprotease-dependent manner. © 2011 Elsevier Inc
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Neuromedin B receptors regulate EGF receptor tyrosine phosphorylation in lung cancer cells
European Journal of Pharmacology, 2010Co-Authors: Terry W. Moody, Samuel A. Mantey, Marc J. Berna, Veronica Sancho, Lisa A. Ridnour, David A. Wink, Daniel Chan, Giuseppe GiacconeAbstract:Neuromedin B (NMB), a member of the bombesin family of peptides, is an autocrine growth factor for many lung cancer cells. The present study investigated the ability of NMB to cause transactivation of the epidermal growth factor (EGF) receptor in lung cancer cells. By Western blot, addition of NMB or related peptides to NCI-H1299 human non-small cell lung cancer (NSCLC) cells, caused phosphorylation of Tyr1068 of the EGF receptor. The signal was amplified using NCI-H1299 cells stably transected with NMB receptors. The transactivation of the EGF receptor or the tyrosine phosphorylation of ERK caused by NMB-like peptides was inhibited by AG1478 or gefitinib (tyrosine kinase inhibitors) and NMB receptor antagonist PD168368 but not the GRP receptor antagonist, BW2258U89. The transactivation of the EGF receptor caused by NMB-like peptides was inhibited by GM6001 (matrix metalloprotease inhibitor), PP2 (Src inhibitor), or transforming growth factor (TGF)α antibody. The transactivation of the EGF receptor and the increase in reactive oxygen species caused by NMB-like peptides was inhibited by N-acetylcysteine (NAC) or Tiron. Gefitinib inhibited the proliferation of NCI-H1299 cells and its sensitivity was increased by the addition of PD168368. The results indicate that the NMB receptor regulates EGF receptor transactivation by a mechanism dependent on Src as well as metalloprotease activation and generation of reactive oxygen species.