Nimmanapalli Ramadevi, Bali Purva, O'Bryan Erica, Fuino Lianne, Guo Fei, Wu Jie, Houghton Peter, Bhalla Kapil
Interdisciplinary Oncology Program, Moffitt Cancer Center and Research Institute, University of South Florida, 12902 Magnolia Drive, Tampa, FL 33612, USA.
Cancer Res. 2003 Nov 15;63(22):7950-8.
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.
目前的研究表明，三氧化二砷（AT）治疗可降低异位表达或内源性Bcr-Abl蛋白水平，并诱导表达Bcr-Abl的培养及原代慢性髓性白血病细胞凋亡，包括那些对甲磺酸伊马替尼耐药的细胞。AT治疗既不影响bcr-abl mRNA转录水平，也不促进Bcr-Abl的蛋白酶体降解。重要的是，在[³⁵S]甲硫氨酸标记的白血病细胞中，暴露于AT可迅速降低新合成的Bcr-Abl水平，表明抑制了bcr-abl mRNA翻译。AT治疗可迅速抑制3-磷酸肌醇依赖性蛋白激酶-1以及p70 S6激酶-1的活性。已知p70 S6激酶-1是一组具有长且高度结构化的5'-非翻译区（UTR）并包含一段寡嘧啶（TOP）的mRNA翻译的正调控因子。由于发现bcr-abl mRNA在其5'-UTR中具有长且高度结构化的5'-UTR并包含一个12个嘧啶的TOP序列，我们在异位表达bcr-abl基因5'-UTR缺失突变体的Jurkat细胞（即Jurkat/Bcr-Abl(5'UTR-)细胞）中确定了AT的作用。AT治疗既未降低Bcr-Abl的5'-UTR缺失突变体水平，也未诱导Jurkat/Bcr-Abl(5'UTR-)细胞凋亡。综上所述，这些发现证明了一种新机制，通过该机制AT可下调Bcr-Abl水平并诱导Bcr-Abl阳性慢性髓性白血病细胞凋亡。
