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• W1497994681 abstract "Proc Amer Assoc Cancer Res, Volume 47, 20065435 In previous studies we have shown that topoisomerase II alpha (topo IIa) is exported from the nucleus to the cytoplasm by a CRM1-associated mechanism at high cell densities, similar to those found in multiple myeloma patient (MM) bone marrow (Turner et al, J. Cell Science 117:3061-3071, 2004). Under such conditions, the cells are highly resistant to topo II poisons. We hypothesize that drug resistance depends on topo IIa trafficking to the cytoplasm where it would not be in contact with the DNA, and therefore unable to produce DNA cleavable complexes and subsequent cell death. Based on these findings, we have blocked topo IIa export to determine whether increased nuclear localization of this enzyme would sensitize the cells to VP-16 and doxorubicin. Several methods were used to block topo IIa nuclear export, including leptomycin B (LMB), ratjadone C (RDC), and a pooled siRNA targeted to the mRNA of the export molecule CRM1. RDC and LMB inhibit CRM1 by covalent modification that prevents CRM1 attachment to its cargo protein. The siRNA to CRM1 mRNA was used to deplete total cellular CRM1 protein. All three methods to block nuclear export were found to be effective, as shown by immunofluorescence microscopy, and Western blot of cytoplasmic extracts. CRM1 specific siRNA produced a 50 to 70% knockdown of CRM1 protein. Three human multiple myeloma cell lines, RPMI-8226, H929 and U266, were treated with RDC, LMB, or siRNA and then exposed to the topo II inhibitors, doxorubicin or VP-16 at high cell densities. Cells in which CRM1 was depleted or blocked were found to be four-fold more sensitive to these drugs as determined by caspase 3 apoptosis assays and mitochondrial membrane potential (flow cytometry). Mechanistic studies determined that cell death was due to increased DNA strand breaks, as shown by the comet assay. In addition, band depletion assays showed that the topo II inhibitors, in combination with CRM1 inhibitors, increased the amount of topo IIa that was covalently bound to DNA. This suggests that topo II inhibitor /CRM1 inhibitor treatment increased the level of cleavable complexes by retaining topo IIa in the nucleus, which would lead to more DNA strand breaks and cell death. Thus, blocking topo IIa nuclear export in high-density myeloma cells sensitizes these cells to topo II inhibitors. This may have clinical implications. Supported in part by NIH grant CA82533." @default.
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• W1497994681 date "2006-04-15" @default.
• W1497994681 modified "2023-09-24" @default.
• W1497994681 title "CRM1 knockdown by ratjadone C, leptomycin B, and siRNA to CRM1, enhance sensitivity of human multiple myeloma cells to topoisomerase II inhibitors." @default.
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