Chemotherapy disrupts activity of translational regulatory proteins in bone marrow stromal cells
| Autor: | Suzanne D. Clutter, Laura F. Gibson, James E. Fortney |
|---|---|
| Rok vydání: | 2006 |
| Předmět: |
Antimetabolites
Antineoplastic Cancer Research Stromal cell Translational efficiency Bone Marrow Cells Cell Cycle Proteins Enzyme-Linked Immunosorbent Assay Protein Serine-Threonine Kinases Biology Cell Line Mice Phosphatidylinositol 3-Kinases Structure-Activity Relationship Genetics medicine Lymph node stromal cell Animals Humans Enzyme Inhibitors Phosphorylation Cyclophosphamide Melphalan Molecular Biology Adaptor Proteins Signal Transducing Etoposide Sirolimus Ribosomal Protein S6 TOR Serine-Threonine Kinases Ribosomal Protein S6 Kinases 70-kDa Chemotaxis Cell Biology Hematology Phosphoproteins Molecular biology Haematopoiesis medicine.anatomical_structure Cancer research Matrix Metalloproteinase 2 Bone marrow Stromal Cells Stem cell Protein Kinases Signal Transduction Chemotaxis assay |
| Zdroj: | Experimental Hematology. 34:1522-1531 |
| ISSN: | 0301-472X |
| DOI: | 10.1016/j.exphem.2006.06.021 |
| Popis: | Objective Bone marrow stromal cell function is a critical influence on hematopoietic reconstitution following progenitor or stem cell transplantation. Stromal cells support hematopoietic cell migration, survival, and proliferation. We have previously reported that stromal cell matrix metalloproteinase-2 (MMP-2) is necessary for optimal support of pro-B−cell chemotaxis through its regulation of stromal cell-derived factor-1 (CXCL12) release. Following exposure to the topoisomerase II inhibitor, etoposide (VP-16), stromal cell MMP-2 protein expression is reduced. The current study investigated the mechanism by which VP-16 may alter translation of MMP-2 in bone marrow stromal cells. Materials and Methods Bone marrow stromal cells were exposed to chemotherapeutic agents etoposide, melphalan, and 4-hydroperoxycyclophosphamide (4HC) and evaluated for MMP-2 expression by enzyme-linked immunosorbent assay and support of pro-B−cell chemotaxis by chemotaxis assay. Western blot analyses were completed to evaluate phosphorylation of stromal cell translational regulatory proteins 4E binding protein-1 (4EBP-1), P70 S6K , and S6 or MMP-2 in the presence of chemotherapy, or the chemical inhibitors rapamycin or LY294002. Results Rapid dephosphorylation of 4EBP-1, P70 S6K , and S6 following VP-16 exposure was observed, consistent with blunted translational efficiency. We also observed that inhibition of stromal cell mammalian target of rapamycin with rapamycin, or phosphatidylinositol 3 kinase with LY294002, resulted in inhibition of stromal cell MMP-2 protein. In addition we found that the chemotherapeutic agents melphalan and 4HC disrupt bone marrow stromal cell MMP-2 protein expression and support of chemotaxis. Conclusions These data suggest that one mechanism by which chemotherapy may alter stromal cells of the bone marrow microenvironment is through disrupted translation of proteins. |
| Databáze: | OpenAIRE |
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