The Microtubule-Targeting Agents, PBOX-6 [Pyrrolobenzoxazepine 7-[(dimethylcarbamoyl) oxy]-6-(2-naphthyl) pyrrolo-[2,1-d] (1,5)-benzoxazepine] and Paclitaxel, Induce Nucleocytoplasmic Redistribution of the Peptidyl-Prolyl Isomerases, Cyclophilin A and Pin1, in Malignant Hematopoietic Cells

Microtubule assembly and disassembly is required for the maintenance of cell structure, mobility, and division. However, the cellular and biochemical implications of microtubule disruption are not fully understood. Using a proteomic approach, we found that the peptidyl-prolyl isomerase, cyclophilin A, was increased in plasma membrane extracts from chronic myeloid leukemia cells after microtubule disruption. In addition, we found that two peptidyl-prolyl isomerases, cyclophilin A and pin1, are overexpressed up to 10-fold in hematological malignancies compared with normal peripheral blood mononuclear cells. Although previous reports suggest that cyclophilin A is localized to the cytosol of mammalian cells, we found that cyclophilin A and pin1 are both localized to the nucleus and nuclear domains in hematopoietic cells. Microtubule disruption of hematopoietic cells caused a dramatic subcellular redistribution of cyclophilin A and pin1 from the nucleus to the cytosol and plasma membrane. We suggest that this accounts for the increased cyclophilin A at the plasma membrane of chronic myeloid leukemia cells after microtubule disruption. The subcellular redistribution of cyclophilin A and pin1 occurred in a c-Jun NH2-terminal kinase-and serine protease-dependent manner. Moreover, the altered subcellular localization of the peptidyl-prolyl isomerases occurred in a dose-and time-dependent manner after microtubule disruption and was found to correlate with G(2)/M arrest and precede induced cell death. These results suggest that the function of peptidyl-prolyl isomerases may be influenced by microtubule dynamics throughout the cell cycle, and their altered localization may be an important part of the mechanism by which microtubuledisrupting agents exert their cytostatic effects.