Suppression of proHB-EGF Carboxy-Terminal Fragment Nuclear Translocation: A New Molecular Target Therapy for Gastric Cancer
Copyright policy )Suppression of proHB-EGF Carboxy-Terminal Fragment Nuclear Translocation: A New Molecular Target Therapy for Gastric Cancer
Abstract Purpose: Inactivation of epidermal growth factor (EGF) receptor (EGFR) represents a promising strategy for the development of selective therapies against epithelial cancers and has been extensively studied as a molecular target for cancer therapy. However, little attention has been paid to remnant cell-associated domains created by cleavage of EGFR ligands. The present study focused on recent findings that cleavage of membrane-anchored heparin-binding EGF-like growth factor (proHB-EGF), an EGFR ligand, induces translocation of the carboxyl-terminal fragment (CTF) of HB-EGF from the plasma membrane to the nucleus and regulates cell cycle. Experimental Design: Two gastric cancer cell lines, MKN28 and NUGC4, were used. KB-R7785, an inhibitor of proHB-EGF shedding, was used to suppress HB-EGF-CTF nuclear translocation with cetuximab, which inhibits EGFR phosphorylation. Cell growth was analyzed using 3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium, inner salt assay, apoptosis was evaluated by assay of caspase-3 and caspase-7, and cell cycle was investigated by flow cytometry. Results: Immunofluorescence study confirmed that KB-R7785 inhibited HB-EGF-CTF nuclear translocation under conditions of proHB-EGF shedding induction by 12-O-tetradecanoylphorbol-13-acetate in gastric cancer cells. KB-R7785 inhibited cell growth in a dose-dependent manner and high-dose KB-R7785 induced apoptosis. Moreover, KB-R7785 induced cell cycle arrest and increased sub-G1 DNA content. KB-R7785 suppressed cyclin A and c-Myc expression. All effects of KB-R7785 were reinforced by combination with cetuximab. Conclusions: These results suggest that both inhibition of EGFR phosphorylation and inhibition of HB-EGF-CTF nuclear translocation play crucial roles in inhibitory regulation of cancer cell growth. Suppression of HB-EGF-CTF nuclear translocation might offer a new strategy for treating gastric cancer.
- Nagoya City University Japan
Cell Nucleus, Drug Evaluation, Preclinical, Glycine, Kruppel-Like Transcription Factors, ADAM12 Protein, Antibodies, Monoclonal, Cetuximab, Membrane Proteins, Antibodies, Monoclonal, Humanized, Hydroxamic Acids, Models, Biological, Peptide Fragments, ErbB Receptors, ADAM Proteins, Drug Delivery Systems, Cell Line, Tumor, Antineoplastic Combined Chemotherapy Protocols, Humans, Intercellular Signaling Peptides and Proteins, Heparin-binding EGF-like Growth Factor
Cell Nucleus, Drug Evaluation, Preclinical, Glycine, Kruppel-Like Transcription Factors, ADAM12 Protein, Antibodies, Monoclonal, Cetuximab, Membrane Proteins, Antibodies, Monoclonal, Humanized, Hydroxamic Acids, Models, Biological, Peptide Fragments, ErbB Receptors, ADAM Proteins, Drug Delivery Systems, Cell Line, Tumor, Antineoplastic Combined Chemotherapy Protocols, Humans, Intercellular Signaling Peptides and Proteins, Heparin-binding EGF-like Growth Factor
citations This is an alternative to the "Influence" indicator, which also reflects the overall/total impact of an article in the research community at large, based on the underlying citation network (diachronically).27 popularity This indicator reflects the "current" impact/attention (the "hype") of an article in the research community at large, based on the underlying citation network.Average influence This indicator reflects the overall/total impact of an article in the research community at large, based on the underlying citation network (diachronically).Top 10% impulse This indicator reflects the initial momentum of an article directly after its publication, based on the underlying citation network.Top 10%
Citations provided by BIP!Popularity provided by BIP!