The Experts below are selected from a list of 3636 Experts worldwide ranked by ideXlab platform
Peter M Moyle - One of the best experts on this subject based on the ideXlab platform.
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Gastrin-Releasing Peptide receptor-targeted hybrid Peptide/phospholipid pDNA/siRNA delivery systems
Nanomedicine: Nanotechnology Biology and Medicine, 2019Co-Authors: Anjuman Ara Begum, Istvan Toth, Peter M MoyleAbstract:Aim: To develop a Peptide/phospholipid hybrid system for Gastrin-Releasing Peptide receptor (GRPR)-targeted delivery of pDNA or siRNA. Materials & methods: A multifunctional GRPR-targeted Peptide R-9-K(GALA)-BBN(6-14) was combined with a phospholipid oligonucleotide delivery system (1:1 1,2-dioleoyl-sn-glycero-3-phosphoethanolamine and 1,2-dioleoyl-3-trimethylammonium-propane) and evaluated for pDNA and siRNA delivery in terms of complex size, toxicity, receptor-targeted delivery and gene expression or knockdown efficiency. Results: By combining Peptide and phospholipid delivery systems, synergistic improvements in gene expression and knockdown were observed when compared with either system alone. The optimized formulation demonstrated high levels of EGFP expression and EGFP knockdown, GRPR-targeted delivery, enhanced endosomal release and minimal toxicity. Conclusion: The Peptide/phospholipid hybrid system provides efficient GRPR-targeted DNA/siRNA delivery.
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bombesin oligoarginine fusion Peptides for Gastrin Releasing Peptide receptor grpr targeted gene delivery
Bioorganic & Medicinal Chemistry, 2018Co-Authors: Anjuman Ara Begum, Istvan Toth, Yu Wan, Peter M MoyleAbstract:The development of non-viral gene delivery systems, with the capacity to overcome most of the biological barriers facing gene delivery, is challenging. We have developed Peptide-based, multicomponent, non-viral delivery systems, incorporating: a bombesin Peptide ligand (BBN(6-14)), to selectively target the Gastrin Releasing Peptide receptor (GRPR); oligoarginine Peptides (hexa- (R6) and nona-arginine (R9)), for plasmid DNA (pDNA) condensation; and GALA, to facilitate endosome escape. The uptake and endosome escape efficiency of bombesin/oligoarginine and bombesin/oligoarginine/GALA fusion Peptides for oligonucleotide delivery was evaluated in terms of their complex size, cellular uptake, endosome escape, and cellular toxicity. Complex size and cell uptake studies demonstrated that the nona-arginine/bombesin delivery system was more efficient at condensing and delivering pDNA into PC-3 prostate cancer cells compared to the hexa-arginine/bombesin delivery system. Further, competition with free bombesin Peptide, and comparative uptake studies in Caco-2 cells, which express GRPR at a lower level, suggested that GRPR contributes to the targeted uptake of this system. The addition of GALA into the nona-arginine/bombesin-based system further increased the pDNA cellular uptake at all tested N/P ratios; facilitated endosomal pDNA release; and had limited effects on cell viability. In conclusion, the delivery system combining BBN(6-14) with nona-arginine and GALA had optimal characteristics for the delivery of pDNA into the GRPR overexpressing cell line PC-3.
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Bombesin/oligoarginine fusion Peptides for Gastrin Releasing Peptide receptor (GRPR) targeted gene delivery.
Bioorganic & Medicinal Chemistry, 2017Co-Authors: Anjuman Ara Begum, Istvan Toth, Peter M MoyleAbstract:Abstract The development of non-viral gene delivery systems, with the capacity to overcome most of the biological barriers facing gene delivery, is challenging. We have developed Peptide-based, multicomponent, non-viral delivery systems, incorporating: a bombesin Peptide ligand (BBN(6–14)), to selectively target the Gastrin Releasing Peptide receptor (GRPR); oligoarginine Peptides (hexa- (R6) and nona-arginine (R9)), for plasmid DNA (pDNA) condensation; and GALA, to facilitate endosome escape. The uptake and endosome escape efficiency of bombesin/oligoarginine and bombesin/oligoarginine/GALA fusion Peptides for oligonucleotide delivery was evaluated in terms of their complex size, cellular uptake, endosome escape, and cellular toxicity. Complex size and cell uptake studies demonstrated that the nona-arginine/bombesin delivery system was more efficient at condensing and delivering pDNA into PC-3 prostate cancer cells compared to the hexa-arginine/bombesin delivery system. Further, competition with free bombesin Peptide, and comparative uptake studies in Caco-2 cells, which express GRPR at a lower level, suggested that GRPR contributes to the targeted uptake of this system. The addition of GALA into the nona-arginine/bombesin-based system further increased the pDNA cellular uptake at all tested N/P ratios; facilitated endosomal pDNA release; and had limited effects on cell viability. In conclusion, the delivery system combining BBN(6–14) with nona-arginine and GALA had optimal characteristics for the delivery of pDNA into the GRPR overexpressing cell line PC-3.
Jill M. Siegfried - One of the best experts on this subject based on the ideXlab platform.
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Elevated Gastrin-Releasing Peptide receptor mRNA expression in buccal mucosa: association with head and neck squamous cell carcinoma.
Head and Neck-journal for The Sciences and Specialties of The Head and Neck, 2012Co-Authors: Ann Marie Egloff, Jill M. Siegfried, Autumn Gaither Davis, Brian K. Trevelline, Marike Vuga, Jennifer R. GrandisAbstract:Background. Expression of Gastrin-Releasing Peptide receptor (GRPR) is elevated in mucosa adjacent to head and neck squamous cell carcinoma (HNSCC) compared with mucosa from cancer-free controls, suggesting elevated GRPR expression may indicate presence of HNSCC. Methods. We measured GRPR mRNA levels in histologically normal buccal mucosa from 65 surgical patients with HNSCC and 75 cancer- free control subjects using quantitative polymerase chain reaction (PCR). We tested for association between GRPR expression and HNSCC and evaluated differences in patient progression-free survival (PFS). Results. Buccal GRPR expression was higher in cases but not controls who were active smokers (p ¼ .04). High GRPR expression was
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Gastrin Releasing Peptide activates akt through the epidermal growth factor receptor pathway and abrogates the effect of gefitinib
Experimental Cell Research, 2007Co-Authors: Xuwan Liu, Jennifer R. Grandis, Diane L Carlisle, Michelle C Swick, Autumn Gaitherdavis, Jill M. SiegfriedAbstract:Gastrin-Releasing Peptide (GRP) is a mitogen for lung epithelial cells and initiates signaling through a G-protein-coupled receptor, Gastrin-Releasing Peptide receptor (GRPR). Because GRPR transactivates the epidermal growth factor receptor (EGFR), we investigated induction by GRP of Akt, an EGFR-activated signaling pathway, and examined effects of GRP on viability of non-small cell lung carcinoma (NSCLC) cells exposed to the EGFR tyrosine kinase inhibitor gefitinib. GRP induced Akt activation primarily through c-Src-mediated transactivation of EGFR. Transfection of dominant-negative c-Src abolished GRP-induced EGFR and Akt activation. GRP induced release of amphiregulin, and pre-incubation with human amphiregulin neutralizing antibody eliminated GRP-induced Akt phosphorylation. Pretreatment with phosphatidylinositol 3-kinase (PI3K) inhibitor LY294002 completely blocked GRP-initiated Akt phosphorylation. These results suggest that GRP stimulates Akt activation primarily via c-Src activation, followed by extracellular release of the EGFR ligand amphiregulin, leading to the activation of EGFR and PI3K. Pretreatment of NSCLC cells with GRP resulted in an increase in the IC50 of gefitinib of up to 9-fold; this protective effect was mimicked by the pretreatment of cells with amphiregulin and reversed by Akt or PI3K inhibition. GRP appears to rescue NSCLC cells exposed to gefitinib through release of amphiregulin and activation of the Akt pathway, suggesting GRPR and/or EGFR autocrine pathways in NSCLC cells may modulate therapeutic response to EGFR inhibitors.
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antitumor mechanisms of combined Gastrin Releasing Peptide receptor and epidermal growth factor receptor targeting in head and neck cancer
Molecular Cancer Therapeutics, 2007Co-Authors: Qing Zhang, Jill M. Siegfried, Neil E Bhola, Vivian Wai Yan Lui, Doris R Siwak, Sufi M Thomas, Christopher T Gubish, Gordon B Mills, Dong M Shin, Jennifer R. GrandisAbstract:Head and neck squamous cell carcinoma (HNSCC) is characterized by epidermal growth factor receptor (EGFR) overexpression, where EGFR levels correlate with survival. To date, EGFR targeting has shown limited antitumor effects in head and neck cancer when administrated as monotherapy. We previously identified a Gastrin-Releasing Peptide/Gastrin-Releasing Peptide receptor (GRP/GRPR) aurocrine regulatory pathway in HNSCC, where GRP stimulates Src-dependent cleavage of EGFR proligands with subsequent EGFR phosphorylation and mitogen-activated protein kinase (MAPK) activation. To determine whether GRPR targeting can enhance the antitumor efficacy of EGFR inhibition, we investigated the effects of a GRPR antagonist (PD176252) in conjunction with an EGFR tyrosine kinase inhibitor (erlotinib). Combined blockade of GRPR and EGFR pathways significantly inhibited HNSCC, but not immortalized mucosal epithelial cell, proliferation, invasion, and colony formation. In addition, the percentage of apoptotic cells increased upon combined inhibition. The enhanced antitumor efficacy was accompanied by increased expression of cleaved poly(ADP-ribose) polymerase (PARP) and decreased phospho-EGFR, phospho-MAPK, and proliferating cell nuclear antigen (PCNA). Using reverse-phase protein microarray (RPPA), we further detected decreased expression of phospho-c-Jun, phospho-p70S6K, and phospho-p38 with combined targeting. Cumulatively, these results suggest that GRPR targeting can enhance the antitumor effects of EGFR inhibitors in head and neck cancer.
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mitogenic effects of Gastrin Releasing Peptide in head and neck squamous cancer cells are mediated by activation of the epidermal growth factor receptor
Oncogene, 2003Co-Authors: Vivian Wai Yan Lui, Jill M. Siegfried, Qing Zhang, Sufi M Thomas, Abbey L Wentzel, Jennifer R. GrandisAbstract:Head and neck squamous cell carcinomas (HNSCC) are characterized by upregulation of the epidermal growth factor receptor (EGFR), where EGFR serves as a potential therapeutic target. We previously reported that a Gastrin-Releasing Peptide/Gastrin-Releasing Peptide receptor (GRP/GRPR) autocrine growth pathway is activated early in HNSCC carcinogenesis. In the present study, we examined the mechanism of EGFR activation by GRP/GRPR in HNSCC proliferation. In HNSCC cells that express elevated levels of both GRPR and EGFR, we found that GRP induced rapid phosphorylation of EGFR as well as p44/42-MAPK activation. Using several EGFR-specific tyrosine kinase inhibitors and cells derived from EGFR knockout mice, we demonstrated that GRP-induced p44/42-MAPK activation was dependent upon EGFR activation. Further investigation demonstrated that cleavage of transforming growth factor-alpha (TGF-α) by matrix metalloproteinases mediated GRP-induced MAPK activation. In addition, HNSCC proliferation stimulated by GRP was eliminated upon specific inhibition of EGFR or MEK, and GRP failed to stimulate proliferation in EGFR-deficient cells. These results imply that the mitogenic effects of GRP in HNSCC are mediated by extracellular release of TGF-α and require the activation of an EGFR-dependent MEK/MAPK-dependent pathway.
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sex specific expression of Gastrin Releasing Peptide receptor relationship to smoking history and risk of lung cancer
Journal of the National Cancer Institute, 2000Co-Authors: Sharon P Shriver, Autumn Gaither Davis, Christopher T Gubish, Heather A Bourdeau, Dayna L Tirpak, James D Luketich, Jill M. SiegfriedAbstract:Background: Activation of Gastrin-Releasing Peptide receptor (GRPR) in human airways has been associated with a proliferative response of bronchial cells to Gastrin-Releasing Peptide and with long-term tobacco use. The GRPR gene is located on the X chromosome and escapes X-chromosome inactivation, which occurs in females. Increasing evidence demonstrates that women are more susceptible than men to tobacco carcinogenesis. We hypothesized that the susceptibility of women to the effects of tobacco may be associated with airway expression of GRPR. Methods: We analyzed GRPR messenger RNA (mRNA) expression in lung tissues and cultured airway cells from 78 individuals (40 males and 38 females) and in lung fibroblasts exposed to nicotine in vitro. Nicotinic acetylcholine receptors in airway cells were assayed by use of radioactively labeled nicotine and nicotine antagonists. A polymorphism in exon 2 of the GRPR gene was used to detect allele-specific GRPR mRNA expression in some individuals. Statistical tests were two-sided. Results: GRPR mRNA expression was detected in airway cells and tissues of more female than male nonsmokers (55% versus 0%) and short-term smokers (1‐25 pack-years [pack-years = number of packs of cigarettes smoked per day multiplied by the number of years of smoking]) (75% versus 20%) (P = .018 for nonsmoking and short-term smoking females versus nonsmoking and short-term smoking males). Female smokers exhibited expression of GRPR mRNA at a lower mean pack-year exposure than male smokers (37.4 pack-years versus 56.3 pack-years; P = .037). Lung fibroblasts and bronchial epithelial cells exhibited high-affinity, saturable nicotinic acetylcholine-binding sites. Expression of GRPR mRNA in lung fibroblasts was elevated following exposure to nicotine. Conclusions: Our results suggest that the GRPR gene is expressed more frequently in women than in men in the absence of smoking and that expression of this gene is activated earlier in women in response to tobacco exposure. The presence of two expressed copies of the GRPR gene in females may be a factor in the increased susceptibility of women to tobacco-induced lung cancer. [J Natl Cancer Inst 2000;92:24‐33]
Andrei Iagaru - One of the best experts on this subject based on the ideXlab platform.
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imaging the distribution of Gastrin Releasing Peptide receptors in cancer
The Journal of Nuclear Medicine, 2020Co-Authors: Lucia Baratto, Heying Duan, Helmut R Macke, Andrei IagaruAbstract:Targeting tumor-expressed receptors using selective molecules for diagnostic, therapeutic, or both diagnostic and therapeutic (theragnostic) purposes is a promising approach in oncologic applications. Such approaches have increased significantly over the past decade. Peptides such as Gastrin-Releasing Peptide receptors targeting radiopharmaceuticals are small molecules with fast blood clearance and urinary excretion. They demonstrate good tissue diffusion, low immunogenicity, and highly selective binding to their target cell-surface receptors. They are also easily produced. Gastrin-Releasing Peptide receptors, part of the bombesin family, are overexpressed in many tumors, including breast and prostate cancer, and therefore represent an attractive target for future development.
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Imaging Gastrin-Releasing Peptide receptors (GRPRs) in prostate cancer
Clinical and Translational Imaging, 2018Co-Authors: Lucia Baratto, Riccardo Laudicella, Maria Picchio, Sergio Baldari, Andrei IagaruAbstract:Despite significant advances in detection and treatment, prostate cancer (PC) remains the most common malignancy and a major cause of cancer death in men worldwide. Imaging is critically important for the diagnosis, staging, and management of men with prostate cancer (PC). The conventional imaging modalities have been employed for local and metastatic staging with limited performance. Whole-body positron emission tomography (PET) using prostate membrane antigen-based tracers is the most widely used in research and clinical applications in this scenario. However, other ways to image PC are available. Here, we review the clinical literatures on the use of Gastrin-Releasing Peptide receptors (GRPRs) as targets for imaging patients with PC.
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Prostate Cancer Theranostics Targeting Gastrin-Releasing Peptide Receptors
Molecular Imaging and Biology, 2018Co-Authors: Lucia Baratto, Hossein Jadvar, Andrei IagaruAbstract:Gastrin-Releasing Peptide receptors (GRPRs), part of the bombesin (BBN) family, are aberrantly overexpressed in many cancers, including those of the breast, prostate, pancreas, and lung, and therefore present an attractive target for cancer diagnosis and therapy. Different bombesin analogs have been radiolabeled and used for imaging diagnosis, staging, evaluation of biochemical recurrence, and assessment of metastatic disease in patients with prostate cancer. Recently, interest has shifted from BBN-like receptor agonists to antagonists, because the latter does not induce adverse effects and demonstrate superior in vivo pharmacokinetics. We review the preclinical and clinical literatures on the use of GRPRs as targets for imaging and therapy of prostate cancer, with a focus on the newer developments and theranostic potential of GRPR Peptides.
Anjuman Ara Begum - One of the best experts on this subject based on the ideXlab platform.
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Gastrin-Releasing Peptide receptor-targeted hybrid Peptide/phospholipid pDNA/siRNA delivery systems
Nanomedicine: Nanotechnology Biology and Medicine, 2019Co-Authors: Anjuman Ara Begum, Istvan Toth, Peter M MoyleAbstract:Aim: To develop a Peptide/phospholipid hybrid system for Gastrin-Releasing Peptide receptor (GRPR)-targeted delivery of pDNA or siRNA. Materials & methods: A multifunctional GRPR-targeted Peptide R-9-K(GALA)-BBN(6-14) was combined with a phospholipid oligonucleotide delivery system (1:1 1,2-dioleoyl-sn-glycero-3-phosphoethanolamine and 1,2-dioleoyl-3-trimethylammonium-propane) and evaluated for pDNA and siRNA delivery in terms of complex size, toxicity, receptor-targeted delivery and gene expression or knockdown efficiency. Results: By combining Peptide and phospholipid delivery systems, synergistic improvements in gene expression and knockdown were observed when compared with either system alone. The optimized formulation demonstrated high levels of EGFP expression and EGFP knockdown, GRPR-targeted delivery, enhanced endosomal release and minimal toxicity. Conclusion: The Peptide/phospholipid hybrid system provides efficient GRPR-targeted DNA/siRNA delivery.
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bombesin oligoarginine fusion Peptides for Gastrin Releasing Peptide receptor grpr targeted gene delivery
Bioorganic & Medicinal Chemistry, 2018Co-Authors: Anjuman Ara Begum, Istvan Toth, Yu Wan, Peter M MoyleAbstract:The development of non-viral gene delivery systems, with the capacity to overcome most of the biological barriers facing gene delivery, is challenging. We have developed Peptide-based, multicomponent, non-viral delivery systems, incorporating: a bombesin Peptide ligand (BBN(6-14)), to selectively target the Gastrin Releasing Peptide receptor (GRPR); oligoarginine Peptides (hexa- (R6) and nona-arginine (R9)), for plasmid DNA (pDNA) condensation; and GALA, to facilitate endosome escape. The uptake and endosome escape efficiency of bombesin/oligoarginine and bombesin/oligoarginine/GALA fusion Peptides for oligonucleotide delivery was evaluated in terms of their complex size, cellular uptake, endosome escape, and cellular toxicity. Complex size and cell uptake studies demonstrated that the nona-arginine/bombesin delivery system was more efficient at condensing and delivering pDNA into PC-3 prostate cancer cells compared to the hexa-arginine/bombesin delivery system. Further, competition with free bombesin Peptide, and comparative uptake studies in Caco-2 cells, which express GRPR at a lower level, suggested that GRPR contributes to the targeted uptake of this system. The addition of GALA into the nona-arginine/bombesin-based system further increased the pDNA cellular uptake at all tested N/P ratios; facilitated endosomal pDNA release; and had limited effects on cell viability. In conclusion, the delivery system combining BBN(6-14) with nona-arginine and GALA had optimal characteristics for the delivery of pDNA into the GRPR overexpressing cell line PC-3.
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Bombesin/oligoarginine fusion Peptides for Gastrin Releasing Peptide receptor (GRPR) targeted gene delivery.
Bioorganic & Medicinal Chemistry, 2017Co-Authors: Anjuman Ara Begum, Istvan Toth, Peter M MoyleAbstract:Abstract The development of non-viral gene delivery systems, with the capacity to overcome most of the biological barriers facing gene delivery, is challenging. We have developed Peptide-based, multicomponent, non-viral delivery systems, incorporating: a bombesin Peptide ligand (BBN(6–14)), to selectively target the Gastrin Releasing Peptide receptor (GRPR); oligoarginine Peptides (hexa- (R6) and nona-arginine (R9)), for plasmid DNA (pDNA) condensation; and GALA, to facilitate endosome escape. The uptake and endosome escape efficiency of bombesin/oligoarginine and bombesin/oligoarginine/GALA fusion Peptides for oligonucleotide delivery was evaluated in terms of their complex size, cellular uptake, endosome escape, and cellular toxicity. Complex size and cell uptake studies demonstrated that the nona-arginine/bombesin delivery system was more efficient at condensing and delivering pDNA into PC-3 prostate cancer cells compared to the hexa-arginine/bombesin delivery system. Further, competition with free bombesin Peptide, and comparative uptake studies in Caco-2 cells, which express GRPR at a lower level, suggested that GRPR contributes to the targeted uptake of this system. The addition of GALA into the nona-arginine/bombesin-based system further increased the pDNA cellular uptake at all tested N/P ratios; facilitated endosomal pDNA release; and had limited effects on cell viability. In conclusion, the delivery system combining BBN(6–14) with nona-arginine and GALA had optimal characteristics for the delivery of pDNA into the GRPR overexpressing cell line PC-3.
Jennifer R. Grandis - One of the best experts on this subject based on the ideXlab platform.
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Elevated Gastrin-Releasing Peptide receptor mRNA expression in buccal mucosa: association with head and neck squamous cell carcinoma.
Head and Neck-journal for The Sciences and Specialties of The Head and Neck, 2012Co-Authors: Ann Marie Egloff, Jill M. Siegfried, Autumn Gaither Davis, Brian K. Trevelline, Marike Vuga, Jennifer R. GrandisAbstract:Background. Expression of Gastrin-Releasing Peptide receptor (GRPR) is elevated in mucosa adjacent to head and neck squamous cell carcinoma (HNSCC) compared with mucosa from cancer-free controls, suggesting elevated GRPR expression may indicate presence of HNSCC. Methods. We measured GRPR mRNA levels in histologically normal buccal mucosa from 65 surgical patients with HNSCC and 75 cancer- free control subjects using quantitative polymerase chain reaction (PCR). We tested for association between GRPR expression and HNSCC and evaluated differences in patient progression-free survival (PFS). Results. Buccal GRPR expression was higher in cases but not controls who were active smokers (p ¼ .04). High GRPR expression was
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Gastrin Releasing Peptide activates akt through the epidermal growth factor receptor pathway and abrogates the effect of gefitinib
Experimental Cell Research, 2007Co-Authors: Xuwan Liu, Jennifer R. Grandis, Diane L Carlisle, Michelle C Swick, Autumn Gaitherdavis, Jill M. SiegfriedAbstract:Gastrin-Releasing Peptide (GRP) is a mitogen for lung epithelial cells and initiates signaling through a G-protein-coupled receptor, Gastrin-Releasing Peptide receptor (GRPR). Because GRPR transactivates the epidermal growth factor receptor (EGFR), we investigated induction by GRP of Akt, an EGFR-activated signaling pathway, and examined effects of GRP on viability of non-small cell lung carcinoma (NSCLC) cells exposed to the EGFR tyrosine kinase inhibitor gefitinib. GRP induced Akt activation primarily through c-Src-mediated transactivation of EGFR. Transfection of dominant-negative c-Src abolished GRP-induced EGFR and Akt activation. GRP induced release of amphiregulin, and pre-incubation with human amphiregulin neutralizing antibody eliminated GRP-induced Akt phosphorylation. Pretreatment with phosphatidylinositol 3-kinase (PI3K) inhibitor LY294002 completely blocked GRP-initiated Akt phosphorylation. These results suggest that GRP stimulates Akt activation primarily via c-Src activation, followed by extracellular release of the EGFR ligand amphiregulin, leading to the activation of EGFR and PI3K. Pretreatment of NSCLC cells with GRP resulted in an increase in the IC50 of gefitinib of up to 9-fold; this protective effect was mimicked by the pretreatment of cells with amphiregulin and reversed by Akt or PI3K inhibition. GRP appears to rescue NSCLC cells exposed to gefitinib through release of amphiregulin and activation of the Akt pathway, suggesting GRPR and/or EGFR autocrine pathways in NSCLC cells may modulate therapeutic response to EGFR inhibitors.
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antitumor mechanisms of combined Gastrin Releasing Peptide receptor and epidermal growth factor receptor targeting in head and neck cancer
Molecular Cancer Therapeutics, 2007Co-Authors: Qing Zhang, Jill M. Siegfried, Neil E Bhola, Vivian Wai Yan Lui, Doris R Siwak, Sufi M Thomas, Christopher T Gubish, Gordon B Mills, Dong M Shin, Jennifer R. GrandisAbstract:Head and neck squamous cell carcinoma (HNSCC) is characterized by epidermal growth factor receptor (EGFR) overexpression, where EGFR levels correlate with survival. To date, EGFR targeting has shown limited antitumor effects in head and neck cancer when administrated as monotherapy. We previously identified a Gastrin-Releasing Peptide/Gastrin-Releasing Peptide receptor (GRP/GRPR) aurocrine regulatory pathway in HNSCC, where GRP stimulates Src-dependent cleavage of EGFR proligands with subsequent EGFR phosphorylation and mitogen-activated protein kinase (MAPK) activation. To determine whether GRPR targeting can enhance the antitumor efficacy of EGFR inhibition, we investigated the effects of a GRPR antagonist (PD176252) in conjunction with an EGFR tyrosine kinase inhibitor (erlotinib). Combined blockade of GRPR and EGFR pathways significantly inhibited HNSCC, but not immortalized mucosal epithelial cell, proliferation, invasion, and colony formation. In addition, the percentage of apoptotic cells increased upon combined inhibition. The enhanced antitumor efficacy was accompanied by increased expression of cleaved poly(ADP-ribose) polymerase (PARP) and decreased phospho-EGFR, phospho-MAPK, and proliferating cell nuclear antigen (PCNA). Using reverse-phase protein microarray (RPPA), we further detected decreased expression of phospho-c-Jun, phospho-p70S6K, and phospho-p38 with combined targeting. Cumulatively, these results suggest that GRPR targeting can enhance the antitumor effects of EGFR inhibitors in head and neck cancer.
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mitogenic effects of Gastrin Releasing Peptide in head and neck squamous cancer cells are mediated by activation of the epidermal growth factor receptor
Oncogene, 2003Co-Authors: Vivian Wai Yan Lui, Jill M. Siegfried, Qing Zhang, Sufi M Thomas, Abbey L Wentzel, Jennifer R. GrandisAbstract:Head and neck squamous cell carcinomas (HNSCC) are characterized by upregulation of the epidermal growth factor receptor (EGFR), where EGFR serves as a potential therapeutic target. We previously reported that a Gastrin-Releasing Peptide/Gastrin-Releasing Peptide receptor (GRP/GRPR) autocrine growth pathway is activated early in HNSCC carcinogenesis. In the present study, we examined the mechanism of EGFR activation by GRP/GRPR in HNSCC proliferation. In HNSCC cells that express elevated levels of both GRPR and EGFR, we found that GRP induced rapid phosphorylation of EGFR as well as p44/42-MAPK activation. Using several EGFR-specific tyrosine kinase inhibitors and cells derived from EGFR knockout mice, we demonstrated that GRP-induced p44/42-MAPK activation was dependent upon EGFR activation. Further investigation demonstrated that cleavage of transforming growth factor-alpha (TGF-α) by matrix metalloproteinases mediated GRP-induced MAPK activation. In addition, HNSCC proliferation stimulated by GRP was eliminated upon specific inhibition of EGFR or MEK, and GRP failed to stimulate proliferation in EGFR-deficient cells. These results imply that the mitogenic effects of GRP in HNSCC are mediated by extracellular release of TGF-α and require the activation of an EGFR-dependent MEK/MAPK-dependent pathway.
