Abstract 1511: mda-7/IL-24 potently induces apoptosis in human leukemia cells through a process involving induction of ER stress

Abstract

mda-7/IL-24, a member of the IL-10 cytokine gene family, has been shown to induce cell death in various epithelial cancer cell types while exhibiting relatively little toxicity toward normal cells. Currently, the effects of mda7/IL-24 on myeloid leukemia cells (AML) have not been extensively characterized. In the present study, we report that treatment with recombinant GST-mda7/IL24 strikingly induces apoptosis in diverse myeloid leukemia cell lines including U937, MV4-11, EOL-1 (both FLT3 mutant), and MLL/ENL cells, which display certain leukemia stem cell-like properties. In addition, mda7/IL24 potently induces apoptosis in and suppresses the colony formation capacity (L-CFU) of primary blasts isolated from multiple patients with AML. In contrast, mda-7/IL-24 exerted only minimal effects on normal CD34+ progenitor cells. These effects were associated with profound mitochondrial injury manifested by cytochrome c and AIF release into the cytosol, caspase-3 activation, and PARP cleavage. The apoptotic effects of mda7/IL24 were associated with a potent induction of ER stress in leukemia cell lines as well as in primary AML blasts, manifested by accumulation of GADD153/CHOP, GADD34, GRP78, and IRE1α. Notably molecular studies with shRNA directed against IRE1α revealed that knockdown of IRE1α significantly enhanced mda7/IL24-mediated apoptosis in U937 cells, suggesting that induction of IRE1α plays a protective role against mda7/IL24 lethality. In addition treatment with mda7/IL24 resulted in down-regulation of the anti-apoptotic protein Mcl-1, and marked accumulation of the pro-apoptotic proteins Bim and Noxa. Notably, ectopic expression of Mcl-1 or knock-down of Bim or Noxa with shRNA markedly decreased mda7/IL24-mediated cell death in leukemia cells. Collectively, these findings indicate that mda7/IL24 strikingly induces apoptosis in human myeloid leukemia through a process that involves ER stress induction, Mcl-1 downregulation, and Bim and Noxa upregulation. They also suggest that mda7/IL24 warrants attention as a potential addition to the therapeutic armamentarium in leukemia and possibly other hematologic malignancies. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 1511.

Targeting breast cancer-initiating/stem cells with melanoma differentiation-associated gene-7/interleukin-24

“…We now demonstrate that MDA‐7/IL‐24 induces apoptosis and ER stress in breast cancer‐initiating/stem cells making this therapeutic cytokine an attractive and beneficial option for targeting cancer‐initiating/stem cells . Similar to epithelial tumor cells and leukemia cells, Ad. mda ‐7 triggers a response classically associated with ER stress induction, including upregulation of BiP/GRP78, GRP94 and GADD153, as well as eIF2α phosphorylation, in various breast cancer‐initiating/stem cells.…”

“…29,33 We now demonstrate that MDA-7/IL-24 induces apoptosis and ER stress in breast cancer-initiating/stem cells making this therapeutic cytokine an attractive and beneficial option for targeting cancer-initiating/stem cells. 44 Similar to epithelial tumor cells 14,28 and leukemia cells, 45 Ad.mda-7 Cancer Therapy triggers a response classically associated with ER stress induction, including upregulation of BiP/GRP78, GRP94 and GADD153, as well as eIF2a phosphorylation, in various breast cancer-initiating/stem cells. These findings indicate that the same genetic/epigenetic changes that elicit tumor cell sensitivity to mda-7/IL-24 are maintained in the entire tumor population (both breast cancer non-stem and stem cells), which is important for developing effective therapies for breast cancer.…”