The anti-leukemic activity of sodium dichloroacetate in p53mutated/null cells is mediated by a p53-independent ILF3/p21 pathway

Chiara Agnoletto, Laura Brunelli, Elisabetta Melloni, Roberta Pastorelli, Fabio Casciano, Erika Rimondi, Gian Matteo Rigolin, Antonio Cuneo, Paola Secchiero, Giorgio Zauli

Research output: Contribution to journalArticlepeer-review

Abstract

B-chronic lymphocytic leukemia (B-CLL) patients harboring p53 mutations are invariably refractory to therapies based on purine analogues and have limited treatment options and poor survival. Having recently demonstrated that the mitochondria-targeting small molecule sodium dichloroacetate (DCA) exhibits anti-leukemic activity in p53wild-type B-CLL cells, the aim of this study was to evaluate the effect of DCA in p53mutated B-CLL cells and in p53mutated/null leukemic cell lines. DCA exhibited comparable cytotoxicity in p53wild-type and p53mutated B-CLL patient cell cultures, as well as in p53mutated B leukemic cell lines (MAVER, MEC-1, MEC-2). At the molecular level, DCA promoted the transcriptional induction of p21 in all leukemic cell types investigated, including p53null HL-60. By using a proteomic approach, we demonstrated that DCA up-regulated the ILF3 transcription factor, which is a known regulator of p21 expression. The role of the ILF3/p21 axis in mediating the DCA anti-leukemic activity was underscored by knocking-down experiments. Indeed, transfection with ILF3 and p21 siRNAs significantly decreased both the DCA-induced p21 expression and the DCA-mediated cytotoxicity. Taken together, our results emphasize that DCA is a small molecule that merits further evaluation as a therapeutic agent also for p53mutated leukemic cells, by acting through the induction of a p53-independent pathway.

Original languageEnglish
Pages (from-to)2385-96
Number of pages12
JournalOncotarget
Volume6
Issue number4
DOIs
Publication statusPublished - Feb 10 2015

Keywords

  • Aged
  • Blotting, Western
  • Cell Line, Tumor
  • Cell Survival
  • Cells, Cultured
  • Cyclin-Dependent Kinase Inhibitor p21
  • Dichloroacetic Acid
  • Female
  • Gene Expression Regulation, Leukemic
  • HL-60 Cells
  • Humans
  • Leukemia, Lymphocytic, Chronic, B-Cell
  • Male
  • Middle Aged
  • Models, Genetic
  • Mutation
  • Nuclear Factor 90 Proteins
  • RNA Interference
  • Reverse Transcriptase Polymerase Chain Reaction
  • Tumor Suppressor Protein p53
  • Journal Article

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