Involvement of p53 in alpha4beta1 integrin-mediated resistance of B-CLL cells to fludarabine.
We recently showed that alpha4beta1 integrin induces B-cell chronic lymphocytic leukemia (B-CLL) cell resistance to fludarabine-induced apoptosis via upregulation of Bcl-xL. We have now studied whether p53 was involved in this response. Cells from five B-CLL patients with wild-type p53 determined by DNA sequencing, or from the EHEB cell line, cultured on the alpha4beta1 ligand H/89 during fludarabine treatment, showed significantly higher viability (P<or=0.001) than cells cultured on poly-D-lysine (pLys). Parallel to this different viability, fludarabine increased p53 expression on pLys-cultured cells and this increase was significantly reduced (P<or=0.05) on cells cultured on H/89. Thus, p53 appears to be part of the survival pathway induced by alpha4beta1 ligation and may contribute to the progressive drug resistance in B-CLL.
de la Fuente
María Teresa
MT
Departamento de Inmunologi;a, Centro de Investigaciones Biológicas, CSIC, Madrid, Spain.
Casanova
Benito
B
Cantero
Esperanza
E
Hernández del Cerro
Mercedes
M
Garcia-Marco
José
J
Silva
Augusto
A
Garcia-Pardo
Angeles
A
D000970:Antineoplastic Agents / Q000494:pharmacology; D017209:Apoptosis; D002448:Cell Adhesion; D002470:Cell Survival; D002478:Cells, Cultured; D004305:Dose-Response Relationship, Drug; D019008:Drug Resistance, Neoplasm; D004591:Electrophoresis, Polyacrylamide Gel; D006801:Humans; D015151:Immunoblotting; D039041:Integrin alpha4beta1 / Q000378:metabolism*; D015448:Leukemia, B-Cell / Q000378:metabolism*; D008024:Ligands; D008239:Lysine / Q000737:chemistry; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D017422:Sequence Analysis, DNA; D015398:Signal Transduction; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism / Q000502:physiology*; D015854:Up-Regulation; D014740:Vidarabine / Q000031:analogs & derivatives* / Q000494:pharmacology*; D051020:bcl-X Protein
D000970:Antineoplastic Agents; C494811:BCL2L1 protein, human; D039041:Integrin alpha4beta1; D008024:Ligands; D019253:Proto-Oncogene Proteins c-bcl-2; D016159:Tumor Suppressor Protein p53; D051020:bcl-X Protein; D014740:Vidarabine; D008239:Lysine; C024352:fludarabine