Subject(s)
Focal Adhesions/metabolism , GTPase-Activating Proteins/metabolism , Microfilament Proteins/metabolism , Phosphoric Monoester Hydrolases/metabolism , Tumor Suppressor Proteins/metabolism , Amino Acid Sequence , Animals , Cadherins/genetics , Cadherins/metabolism , Epidermal Growth Factor/genetics , Epidermal Growth Factor/metabolism , GTPase-Activating Proteins/genetics , HeLa Cells , Humans , Mice , Microfilament Proteins/genetics , Molecular Sequence Data , Phosphoric Monoester Hydrolases/genetics , Protein Isoforms/genetics , Protein Isoforms/metabolism , Protein Structure, Tertiary , Rats , Recombinant Fusion Proteins/genetics , Recombinant Fusion Proteins/metabolism , Sequence Alignment , Tensins , Tumor Suppressor Proteins/geneticsABSTRACT
BACKGROUND: 5-Fluorouracil (5-FU) and cisplatin combined chemotherapy (FP) is commonly used for esophageal cancer. Acquired resistance needs to be overcome to improve the chemotherapeutic effect. MATERIALS AND METHODS: The FP-resistant xenograft model using severe combined immunodeficient (SCID) mice was established as an acquired resistance model. RNA was extracted pretreatment, at the onset of the anticancer effect, during the most effective, and regrowth period in the FP administration group and during the mid-progressive period and the far advanced period in the control group. A microarray was applied to explore gene expression changes. RESULTS: The data set containing up-regulated genes in the regrowth period was uploaded into Ingenuity Pathway Analysis. The expression change profiles suggested that activation of not only 5-FU- and cisplatin-specific genes, but also the Phosphoinositide 3-kinase (PI3K)/AKT signal were associated with FP resistance. CONCLUSION: A xenograft model using SCID mice with esophageal cancer cells would monitor gene changes during treatment and regrowth.
Subject(s)
Carcinoma, Squamous Cell/genetics , Drug Resistance, Neoplasm , Esophageal Neoplasms/genetics , Animals , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Biomarkers, Tumor/genetics , Biomarkers, Tumor/metabolism , Carcinoma, Squamous Cell/drug therapy , Carcinoma, Squamous Cell/metabolism , Cisplatin/administration & dosage , Esophageal Neoplasms/drug therapy , Esophageal Neoplasms/metabolism , Fluorouracil/administration & dosage , Gene Expression Profiling , Humans , Mice , Mice, SCID , Oligonucleotide Array Sequence Analysis , Xenograft Model Antitumor AssaysABSTRACT
START-GAP2, also termed as DLC2, is a START domain-containing RhoGAP and a negative regulator of RhoA and Cdc42. Although it was reported as a tumor suppresser gene product, the molecular basis for function of START-GAP2 remains to be clarified. Here, we demonstrate that START-GAP2 is localized in focal adhesions through a "FAT (focal adhesion targeting)" region in the N-terminal half. START-GAP2 competes with START-GAP1/DLC1, another START domain-containing RhoGAP, in focal adhesion targeting. Moreover, the C-terminus of tensin2, one of focal adhesion components and reported to bind START-GAP1, also directly interacts with START-GAP2. These results suggest that START-GAP2 and START-GAP1 share the same molecular mechanism in targeting to focal adhesions.
