Amiloride modulates alternative splicing in leukemic cells and resensitizes Bcr-AblT315I mutant cells to imatinib

Wen Hsin Chang, Ta Chih Liu, Wen Kuang Yang, Chien Chih Lee, Yi Hsiung Lin, Tsai-Yun Chen, Jan Gowth Chang

Research output: Contribution to journalArticle

46 Citations (Scopus)

Abstract

The antihypertensive drug amiloride is being considered as a tactic to improve cancer therapy including that for chronic myelogenous leukemia. In this study, we show that amiloride modulates the alternative splicing of various cancer genes, including Bcl-x, HIPK3, and BCR/ABL, and that this effect is not mainly related to pH alteration, which is a known effect of the drug. Splice modulation involved various splicing factors, with the phosphorylation state of serine-arginine-rich (SR) proteins also altered during the splicing process. Pretreatment with okadaic acid to inhibit protein phosphatase PP1 reversed partially the phosphorylation levels of SR proteins and also the amiloride-modulated yields of Bcl-x s and HIPK3 U(-) isoforms. Genome-wide detection of alternative splicing further revealed that many other apoptotic genes were regulated by amiloride, including APAF-1, CRK, and SURVIVIN. Various proteins of the Bcl-2 family and MAPK kinases were found to be involved in amiloride-induced apoptosis. Moreover, the effect of amiloride on mRNA levels of Bcl-x was demonstrated to translate to the protein levels. Cotreatment of K562 and BaF3/Bcr-AblT315I cells with amiloride and imatinib induced more loss of cell viability than either agent alone. Our findings suggest that amiloride may offer a potential treatment option for chronic myelogenous leukemia either alone or in combination with imatinib.

Original languageEnglish
Pages (from-to)383-392
Number of pages10
JournalCancer Research
Volume71
Issue number2
DOIs
Publication statusPublished - 2011 Jan 15

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Amiloride
Alternative Splicing
Leukemia, Myelogenous, Chronic, BCR-ABL Positive
Serine
Arginine
Proteins
MAP Kinase Kinase 2
Phosphorylation
Okadaic Acid
Imatinib Mesylate
Neoplasm Genes
Phosphoprotein Phosphatases
Antihypertensive Agents
Cell Survival
Protein Isoforms
Genome
Apoptosis
Messenger RNA
Pharmaceutical Preparations

All Science Journal Classification (ASJC) codes

  • Oncology
  • Cancer Research

Cite this

Chang, Wen Hsin ; Liu, Ta Chih ; Yang, Wen Kuang ; Lee, Chien Chih ; Lin, Yi Hsiung ; Chen, Tsai-Yun ; Chang, Jan Gowth. / Amiloride modulates alternative splicing in leukemic cells and resensitizes Bcr-AblT315I mutant cells to imatinib. In: Cancer Research. 2011 ; Vol. 71, No. 2. pp. 383-392.
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Amiloride modulates alternative splicing in leukemic cells and resensitizes Bcr-AblT315I mutant cells to imatinib. / Chang, Wen Hsin; Liu, Ta Chih; Yang, Wen Kuang; Lee, Chien Chih; Lin, Yi Hsiung; Chen, Tsai-Yun; Chang, Jan Gowth.

In: Cancer Research, Vol. 71, No. 2, 15.01.2011, p. 383-392.

Research output: Contribution to journalArticle

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