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Melanoma differentiation associated gene-7/interleukin-24 potently induces apoptosis in human myeloid leukemia cells through a process regulated by endoplasmic reticulum stress Rahmani M; Mayo M; Dash R; Sokhi UK; Dmitriev IP; Sarkar D; Dent P; Curiel DT; Fisher PB; Grant SMol Pharmacol 2010[Dec]; 78 (6): 1096-104Melanoma differentiation associated gene-7 (mda-7)/interleukin-24 (IL-24), a member of the IL-10 cytokine gene family, preferentially induces cell death in neoplastic epithelial cells types while sparing their normal counterparts. The effects of mda-7/IL-24 in acute myeloid leukemia (AML) cells have not been extensively characterized. Treatment with recombinant GST-MDA-7/IL-24 potently induced apoptosis in diverse myeloid leukemia cell types including U937, HL60, MV4-11, EOL-1, and MLL/ENL cells. MDA-7/IL-24 also markedly induced apoptosis in and suppressed the colony-forming capacity of primary AML blasts but exerted minimal toxicity toward normal CD34(+) hematopoietic progenitor cells. MDA-7/IL-24 lethality was associated with pronounced endoplasmic reticulum (ER) stress induction in leukemia cell lines and primary AML blasts, manifested by the accumulation of growth arrest and DNA damage-inducible protein 34 (GADD34), 78-kDa glucose-regulated protein (GRP78)/BiP, inositol-requiring enzyme 1alpha (IRE1alpha), and eukaryotic initiation factor 2alpha phosphorylation. It is noteworthy that short hairpin RNA (shRNA) knockdown of IRE1alpha, GADD34, or GRP78/BiP significantly enhanced MDA-7/IL-24-mediated apoptosis, indicating a protective role for these molecules against MDA-7/IL-24 lethality. MDA-7/IL-24 also down-regulated the antiapoptotic protein Mcl-1 and sharply increased expression of the proapoptotic proteins Bim and Noxa. Ectopic Mcl-1 expression or shRNA knockdown of Bim or Noxa significantly attenuated MDA-7/IL-24-mediated leukemia cell death. Finally, knockdown of Bax or Bak significantly reduced MDA-7/IL-24 lethality. Together, these findings indicate that MDA-7/IL-24 potently induces apoptosis in human myeloid leukemia cells through a process regulated by ER stress induction, Mcl-1 down-regulation, and Bim and Noxa up-regulation. They also suggest that MDA-7/IL-24 warrants further investigation in myeloid leukemia.|Apoptosis/*physiology[MESH]|Cell Differentiation/physiology[MESH]|Cell Transformation, Neoplastic/pathology[MESH]|Cells, Cultured[MESH]|Endoplasmic Reticulum Chaperone BiP[MESH]|Endoplasmic Reticulum/*pathology[MESH]|HL-60 Cells[MESH]|Humans[MESH]|Interleukins/*physiology[MESH]|Leukemia, Myeloid/metabolism/*pathology[MESH]|Stem Cells/pathology[MESH]|Stress, Physiological/*physiology[MESH]|U937 Cells[MESH] |
