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Cancer Res. 2003 Nov 15;63(22):7950-8.

Arsenic trioxide inhibits translation of mRNA of bcr-abl, resulting in attenuation of Bcr-Abl levels and apoptosis of human leukemia cells.

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Interdisciplinary Oncology Program, Moffitt Cancer Center and Research Institute, University of South Florida, 12902 Magnolia Drive, Tampa, FL 33612, USA.


Present studies demonstrate that treatment with arsenic trioxide (AT) lowered ectopically expressed or endogenous levels of Bcr-Abl protein, as well as induced apoptosis of Bcr-Abl-expressing cultured and primary chronic myeloid leukemia cells, including those refractory to imatinib mesylate. Treatment with AT neither affected bcr-abl mRNA transcript levels nor promoted the proteasomal degradation of Bcr-Abl. Importantly, in [(35)S]methionine-labeled leukemia cells, exposure to AT rapidly lowered the levels of the newly synthesized Bcr-Abl, indicating inhibition of bcr-abl mRNA translation. Treatment with AT rapidly inhibited the activity of 3-phosphoinositide-dependent protein kinase-1, as well as of p70 S6 kinase-1. p70 S6 kinase-1 is known to be a positive regulator of the translation of a group of mRNAs that possesses a long and highly structured 5'-untranslated region (UTR) containing a tract of oligopyrimidines (TOP). Because bcr-abl mRNA was discovered to possess a long and highly structured 5'-UTR containing a 12-pyrimidine TOP sequence in its 5'-UTR, we determined the effect of AT in Jurkat cells with ectopic expression of a 5'-UTR-deleted mutant of the bcr-abl gene, i.e., Jurkat/Bcr-Abl (5'UTR-) cells. Treatment with AT neither lowered the levels of the 5'-UTR-deleted mutant of Bcr-Abl nor induced apoptosis of Jurkat/Bcr-Abl (5'UTR-) cells. Taken together, these findings demonstrate a novel mechanism by which AT down-regulates Bcr-Abl levels and induces apoptosis of Bcr-Abl-positive chronic myelogenous leukemia cells.

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