PT - JOURNAL ARTICLE AU - Mohamed Rahmani AU - Mandy Mayo AU - Rupesh Dash AU - Upneet Kaur Sokhi AU - Igor P Dmitriev AU - Devanand Sarkar AU - Paul Dent AU - David T Curiel AU - Paul B Fisher AU - Steven Grant TI - MDA-7/IL-24 potently induces apoptosis in human myeloid leukemia cells through a process regulated by ER stress AID - 10.1124/mol.110.068007 DP - 2010 Sep 21 TA - Molecular Pharmacology PG - mol.110.068007 4099 - http://molpharm.aspetjournals.org/content/early/2010/09/21/mol.110.068007.short 4100 - http://molpharm.aspetjournals.org/content/early/2010/09/21/mol.110.068007.full AB - mda-7/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. Currently, the effects of mda-7/IL-24 in myeloid leukemia cells (AML) have not been extensively characterized. Treatment with recombinant GST-MDA-7/IL-24 potently induced apoptosis in diverse myeloid leukemia cell types including U937, HL-60, MV4-11, EOL-1, and MLL/ENL cells. MDA-7/IL-24 also markedly induced apoptosis in and suppressed the colony forming capacity (L-CFU) of primary AML blasts but exerted minimal toxicity toward normal CD34+ hematopoietic progenitor cells. MDA-7/IL-24 lethality was associated with pronounced ER stress induction in leukemia cell lines and primary AML blasts, manifested by accumulation of GADD34, GRP78/BiP, and IRE1α, and eIF2α phosphorylation. Notably, 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 anti-apoptotic protein Mcl-1 and sharply increased expression of the pro-apoptotic 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. Collectively, 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.