Arsenic Trioxide Inhibits Translation of mRNA of bcr-abl, Resulting in Attenuation of Bcr-Abl Levels and Apoptosis of Human Leukemia Cells

Ramadevi Nimmanapalli, Purva Bali, Erica O'Bryan, Lianne Fuino, Fei Guo, Jie Wu, Peter Houghton, Kapil Bhalla

Research output: Contribution to journalArticle

51 Scopus citations

Abstract

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 [35S]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.

Original languageEnglish (US)
Pages (from-to)7950-7958
Number of pages9
JournalCancer Research
Volume63
Issue number22
StatePublished - Nov 15 2003
Externally publishedYes

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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    Nimmanapalli, R., Bali, P., O'Bryan, E., Fuino, L., Guo, F., Wu, J., Houghton, P., & Bhalla, K. (2003). Arsenic Trioxide Inhibits Translation of mRNA of bcr-abl, Resulting in Attenuation of Bcr-Abl Levels and Apoptosis of Human Leukemia Cells. Cancer Research, 63(22), 7950-7958.