Melanoma differentiation associated gene-7/interleukin-24 potently induces apoptosis in human myeloid leukemia cells through a process regulated by endoplasmic reticulum stress.

Abstract

Melanoma 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 1α (IRE1α), and eukaryotic initiation factor 2α phosphorylation. It is noteworthy that short hairpin RNA (shRNA) knockdown of IRE1α, 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.

• Authors: Mohamed Rahmani, Mandy Mayo, Rupesh Dash, Upneet Kaur Sokhi, Igor P Dmitriev, Devanand Sarkar, Paul Dent, David T Curiel, Paul B Fisher, Steven Grant
• Journal: Molecular pharmacology (Mol Pharmacol) Vol. 78 Issue 6 Pg. 1096-104 (Dec 2010) ISSN: 1521-0111 [Electronic] United States
• PMID: 20858700 (Publication Type: Comparative Study, Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Endoplasmic Reticulum Chaperone BiP
• HSPA5 protein, human
• Interleukins
• interleukin-24

Topics

• Apoptosis (physiology)
• Cell Differentiation (physiology)
• Cell Transformation, Neoplastic (pathology)
• Cells, Cultured
• Endoplasmic Reticulum (pathology)
• Endoplasmic Reticulum Chaperone BiP
• HL-60 Cells
• Humans
• Interleukins (physiology)
• Leukemia, Myeloid (metabolism, pathology)
• Stem Cells (pathology)
• Stress, Physiological (physiology)
• U937 Cells