Biomedical subjects

Vivian Wai Yan Lui

Publications and source records attributed to Vivian Wai Yan Lui.

8 recordsLinked to original sources

PubMed2006

Phosphorylation of TNF-alpha converting enzyme by gastrin-releasing peptide induces amphiregulin release and EGF receptor activation.

G protein-coupled receptors induce EGF receptor (EGFR) signaling, leading to the proliferation and invasion of cancer cells. Elucidation of the mechanism of EGFR activation by G protein-coupled receptors may identify new signaling paradigms. A gastrin-releasing peptide (GRP)/GRP receptor-mediated autocrine pathway was previously described in squamous cell carcinoma of head and neck. In the present study, we demonstrate that TNF-alpha converting enzyme (TACE), a disintegrin and metalloproteinse-17, undergoes a Src-dependent phosphorylation that regulates release of the EGFR ligand amphiregulin upon GRP treatment. Further investigation reveals the phosphatidylinositol 3-kinase (PI3-K) as the intermediate of c-Src and TACE, contributing to their association and TACE phosphorylation. Phosphoinositide-dependent kinase 1 (PDK1), a downstream target of PI3-K, has been identified as the previously undescribed kinase to directly phosphorylate TACE upon GRP treatment. These findings suggest a signaling cascade of GRP-Src-PI3-K-PDK1-TACE-amphiregulin-EGFR with multiple points of interaction, translocation, and phosphorylation. Furthermore, knockdown of PDK1 augmented the antitumor effects of the EGFR inhibitor erlotinib, indicating PDK1 as a therapeutic target to improve the clinical response to EGFR inhibitors.

3-Phosphoinositide-Dependent Protein Kinases↗

PubMed2006

STAT3 as a therapeutic target in head and neck cancer.

The signal transducer and activator of transcription (STAT) proteins relay signals from cytokine receptors and receptor tyrosine kinases on the cell surface to the nucleus, where they affect the transcription of genes involved in normal cell functions, including growth, apoptosis and differentiation. STAT3 has been found to be constitutively active in head and neck squamous cell carcinoma (HNSCC) as well as in other epithelial malignancies. In HNSCC, STAT3 alters the cell cycle, prevents apoptosis, and mediates the proliferation and survival of tumour cells. Several therapeutic approaches are being developed to target STAT3, including molecules that block either dimerisation or DNA binding by STAT3, strategies to decrease STAT3 expression and drugs that inhibit STAT3 function. Strategies that block STAT3 may prove efficacious for cancer treatment.

Animals↗

PubMed2005

Gastrin-releasing peptide receptor mediates activation of the epidermal growth factor receptor in lung cancer cells.

Gastrin-releasing peptide receptor (GRPR) and the epidermal growth factor receptor (EGFR) are expressed in several cancers including non-small cell lung cancer (NSCLC). Here we demonstrate the activation of EGFR by the GRPR ligand, gastrin-releasing peptide (GRP), in NSCLC cells. GRP induced rapid activation of p44/42 MAPK in lung cancer cells through EGFR. GRP-mediated activation of MAPK in NSCLC cells was abrogated by pretreatment with the anti-EGFR-neutralizing antibody, C225. Pretreatment of NSCLC cells with neutralizing antibodies to the EGFR ligands, TGF-A or HB-EGF, also decreased GRP-mediated MAPK activation. On matrix metalloproteinase (MMP) inhibition, GRP failed to activate MAPK in NSCLC cells. EGF and GRP both stimulated NSCLC proliferation, and inhibition of either EGFR or GRPR resulted in cell death. Combining a GRPR antagonist with the EGFR tyrosine kinase inhibitor, gefitinib, resulted in additive cytotoxic effects. Additive effects were seen at gefitinib concentrations from 1 to 18 microM, encompassing the ID50 values of both gefitinib-sensitive and gefitinib-resistant NSCLC cell lines. Because a major effect of GRPR appears to be promoting the release of EGFR ligand, this study suggests that a greater inhibition of cell proliferation may occur by abrogating EGFR ligand release in consort with inhibition of EGFR.

Blotting, Western↗

PubMed2003

Antitumor effects of epidermal growth factor receptor antisense oligonucleotides in combination with docetaxel in squamous cell carcinoma of the head and neck.

PURPOSE: Antisense approaches targeting the epidermal growth factor receptor (EGFR) have been demonstrated to inhibit the growth of squamous cell carcinoma of the head and neck (SCCHN). Docetaxel is an effective chemotherapeutic agent in the treatment of SCCHN. The present study was undertaken to evaluate the antitumor mechanisms of EGFR antisense (AS) oligonucleotides administered in combination with docetaxel in preclinical models of SCCHN. EXPERIMENTAL DESIGN: SCCHN cells lines and xenografts were treated with an EGFR AS oligonucleotide targeting region 760-779 of EGFR mRNA (GenBank accession XM_004738) alone and in combination with docetaxel. Proliferation in vitro and tumor growth in vivo were examined in addition to determinations of EGFR expression and signaling pathways to evaluate antitumor mechanisms. RESULTS: A combination of docetaxel with EGFR AS resulted in increased cytotoxicity compared with treatment with docetaxel plus EGFR sense oligonucleotides or docetaxel alone after 24 h. Tumor volumes were significantly reduced in the mice treated with a combination of intratumoral EGFR AS and systemic docetaxel compared with mice receiving monotherapy. The combination of docetaxel plus EGFR AS resulted in decreased expression levels of EGFR, phosphotyrosine signal transducers and activators of transcription 3, vascular endothelial growth factor, and pAKT compared with expression levels after either treatment alone. CONCLUSIONS: A combination of EGFR AS and docetaxel may be effective in the treatment of SCCHN with a reduced toxicity profile compared with standard chemotherapy regimens.

Animals↗

PubMed2003

Mitogenic effects of gastrin-releasing peptide in head and neck squamous cancer cells are mediated by activation of the epidermal growth factor receptor.

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-alpha) 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-alpha and require the activation of an EGFR-dependent MEK/MAPK-dependent pathway.

Animals↗

PubMed2002

Gastrin-releasing peptide receptor-mediated autocrine growth in squamous cell carcinoma of the head and neck.

BACKGROUND: Gastrin-releasing peptide receptor (GRPR)-mediated autocrine growth appears to be an early marker of susceptibility to tobacco-related lung cancers. Because expression of GRPR, however, has not been reported in squamous cell carcinoma of the head and neck (SCCHN), we investigated its expression and that of its ligand GRP in normal mucosa and SCCHN tissues and the involvement of these proteins in the proliferation of SCCHN cells. METHODS: We assessed GRPR messenger RNA (mRNA) expression in specimens from 25 patients with SCCHN, six control noncancer patients, and 14 SCCHN cell lines by use of quantitative reverse transcriptase-polymerase chain reaction. We used neutralizing GRP monoclonal antibody 2A11 to block the GRP-GRPR interaction in SCCHN cell lines and xenografts and assessed the antibody's effect on proliferation by counting cultured cells or measuring xenograft tumor volume in vivo. All statistical tests were two-sided. RESULTS: Tumor and mucosa tissues, respectively, from SCCHN patients expressed sixfold and fourfold higher levels of GRPR mRNA than normal mucosa tissue from noncancer patients (P<.001). The levels of GRPR expression in the tumor and adjacent normal epithelium of individual patients with SCCHN were correlated (r =.652; P =.001), suggesting that increased GRPR expression is an early event in SCCHN formation. SCCHN cells expressed fivefold higher levels of GRPR mRNA than did cultured normal mucosal epithelial cells (P =.005). GRP stimulated proliferation of SCCHN cells in a dose-dependent fashion (P =.006). Neutralizing GRP monoclonal antibody 2A11 inhibited SCCHN cell proliferation in vitro and in vivo. Median survival was 54 months in patients with higher levels of GRPR mRNA and was not reached in those with lower levels. CONCLUSIONS: GRP and GRPR appear to participate in an autocrine regulatory pathway in SCCHN. Thus, strategies that specifically target GRP and/or GRPR may be effective therapeutic approaches for this disease.

Adult↗

PubMed2002

Systemic administration of naked DNA encoding interleukin 12 for the treatment of human papillomavirus DNA-positive tumor.

Interleukin 12 (IL-12) is one of the most effective and promising cytokines for cancer therapy. Its therapeutic effects have been demonstrated in a variety of tumors in animal models when it is administrated locally or systemically. We describe here a systemic delivery of naked murine IL-12 (mIL-12) gene in vivo. Dose-dependent systemic production of mIL-12, with a serum level up to approximately 20 microg/ml, was observed 24 hr after systemic gene delivery. The apparent half-life in the circulation was about 5 hr. The result of a bioactivity assay (in vitro interferon gamma [IFN-gamma] release) indicated that the gene product in mice was as active as the purified recombinant murine IL-12 protein (rmIL-12). The circulating mIL-12 activated natural killer cells and stimulated IFN-gamma production in vivo. A single administration of mIL-12 gene resulted in prominent regression of established subcutaneous tumor in a human papillomavirus (HPV) DNA-positive tumor model (TC-1) in C57BL/6J mice. The antitumor effect of the single gene dose was comparable to repeated intraperitoneal administration of rmIL-12 (0.5 microg/day for consecutive 5 days). This systemic gene delivery is simple, economical, and highly efficient for the production of large amounts of cytokine in vivo. With this gene delivery method, we have demonstrated the therapeutic potential of IL-12 for the treatment of HPV DNA-positive tumor and the usefulness of the systemic gene delivery for assessing the therapeutic effect of a candidate gene.

Animals↗

PubMedDate not supplied

EGFR-mediated cell cycle regulation.

Cancer is a disease of uncontrolled cell proliferation. The cell cycle provides a crucial platform for coordination between proliferation and cell death. Somatic cells undergo replication and division by traversing the tightly regulated cell cycle. Growth factors play a critical role in initiating signaling events stimulating cell cycle progression, which is crucial for their mitogenic and tumorigenic effects. Epidermal growth factor receptor (EGFR) and its ligands are frequently upregulated in human cancers. The oncogenic effects of EGFR include initiation of DNA synthesis, enhanced cell growth, invasion, and metastasis. Specific abrogation of EGFR results in cell cycle arrest, apoptosis, or dedifferentiaton of cancer cells. Downregulation of EGFR signaling has therapeutic benefit in preclinical and clinical studies. Therefore, better understanding of the mechanisms of regulation and coordination between the cell cycle, cell growth, and cell death will lead to the development of novel cancer therapies.

Animals↗