Melanoma Differentiation Associated Gene-7/Interleukin-24 Potently Induces Apoptosis in Human Myeloid Leukemia Cells through a Process Regulated by Endoplasmic Reticulum Stress

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.

[1]  P. Fisher,et al.  mda-7/IL-24: a unique member of the IL-10 gene family promoting cancer-targeted toxicity. , 2010, Cytokine & growth factor reviews.

[2]  P. Fisher,et al.  Mechanism by which Mcl-1 regulates cancer-specific apoptosis triggered by mda-7/IL-24, an IL-10-related cytokine. , 2010, Cancer research.

[3]  C. Yang,et al.  Inhibition of autophagy induced by overexpression of mda-7/interleukin-24 strongly augments the antileukemia activity in vitro and in vivo , 2010, Cancer Gene Therapy.

[4]  Paul Dent,et al.  The BH3-only protein Bim plays a critical role in leukemia cell death triggered by concomitant inhibition of the PI3K/Akt and MEK/ERK1/2 pathways. , 2009, Blood.

[5]  Qiuyan Wang,et al.  ERAD inhibitors integrate ER stress with an epigenetic mechanism to activate BH3-only protein NOXA in cancer cells , 2009, Proceedings of the National Academy of Sciences.

[6]  J. Aguirre-Ghiso,et al.  Inhibition of eIF2alpha dephosphorylation maximizes bortezomib efficiency and eliminates quiescent multiple myeloma cells surviving proteasome inhibitor therapy. , 2009, Cancer research.

[7]  H. Gary-Gouy,et al.  IL-24 Induces Apoptosis of Chronic Lymphocytic Leukemia B Cells Engaged into the Cell Cycle through Dephosphorylation of STAT3 and Stabilization of p53 Expression , 2008, The Journal of Immunology.

[8]  Xiao-tong Ma,et al.  mda-7/IL-24 inhibits the proliferation of hematopoietic malignancies in vitro and in vivo. , 2008, Experimental hematology.

[9]  M. D. Chang,et al.  GRP78 and Raf‐1 cooperatively confer resistance to endoplasmic reticulum stress‐induced apoptosis , 2008, Journal of cellular physiology.

[10]  P. Dent,et al.  The BH3-only protein Bim plays a critical role in cell death triggered by concomitant inhibition of the PI3K/Akt and MEK/ERK pathways in human leukemia cells , 2008 .

[11]  P. Fisher,et al.  PERK-dependent regulation of MDA-7/IL-24-induced autophagy in primary human glioma cells , 2008, Autophagy.

[12]  C. Yang,et al.  Enhanced antitumor activity by a selective conditionally replicating adenovirus combining with MDA-7/interleukin-24 for B-lymphoblastic leukemia via induction of apoptosis , 2008, Leukemia.

[13]  Chao Zhang,et al.  IRE1 Signaling Affects Cell Fate During the Unfolded Protein Response , 2007, Science.

[14]  Paul Dent,et al.  The Multikinase Inhibitor Sorafenib Induces Apoptosis in Highly Imatinib Mesylate-Resistant Bcr/Abl+ Human Leukemia Cells in Association with Signal Transducer and Activator of Transcription 5 Inhibition and Myeloid Cell Leukemia-1 Down-Regulation , 2007, Molecular Pharmacology.

[15]  D. Saur,et al.  Translational Repression of MCL-1 Couples Stress-induced eIF2α Phosphorylation to Mitochondrial Apoptosis Initiation* , 2007, Journal of Biological Chemistry.

[16]  P. Walter,et al.  Signal integration in the endoplasmic reticulum unfolded protein response , 2007, Nature Reviews Molecular Cell Biology.

[17]  Tomomi Gotoh,et al.  ER Stress Triggers Apoptosis by Activating BH3-Only Protein Bim , 2007, Cell.

[18]  P. Dent,et al.  The Kinase Inhibitor Sorafenib Induces Cell Death through a Process Involving Induction of Endoplasmic Reticulum Stress , 2007, Molecular and Cellular Biology.

[19]  K. Isobe,et al.  GADD34 inhibits mammalian target of rapamycin signaling via tuberous sclerosis complex and controls cell survival under bioenergetic stress. , 2007, International journal of molecular medicine.

[20]  Junying Yuan,et al.  Selective Inhibition of Eukaryotic Translation Initiation Factor 2α Dephosphorylation Potentiates Fatty Acid-induced Endoplasmic Reticulum Stress and Causes Pancreatic β-Cell Dysfunction and Apoptosis* , 2006, Journal of Biological Chemistry.

[21]  P. Walter,et al.  Intracellular signaling by the unfolded protein response. , 2006, Annual review of cell and developmental biology.

[22]  P. Fisher,et al.  mda-7/IL-24: multifunctional cancer-specific apoptosis-inducing cytokine. , 2006, Pharmacology & therapeutics.

[23]  P. Fisher,et al.  BiP/GRP78 is an intracellular target for MDA-7/IL-24 induction of cancer-specific apoptosis. , 2006, Cancer research.

[24]  F. Davi,et al.  High Mda-7 expression promotes malignant cell survival and p38 MAP kinase activation in chronic lymphocytic leukemia , 2006, Leukemia.

[25]  P. Fisher.  Is mda-7/IL-24 a "magic bullet" for cancer? , 2005, Cancer research.

[26]  P. Dent,et al.  Apoptosis Induced by the Kinase Inhibitor BAY 43-9006 in Human Leukemia Cells Involves Down-regulation of Mcl-1 through Inhibition of Translation* , 2005, Journal of Biological Chemistry.

[27]  Paul Dent,et al.  MDA‐7/IL‐24 regulates proliferation, invasion and tumor cell radiosensitivity: A new cancer therapy? , 2005, Journal of cellular biochemistry.

[28]  T. Kuwana,et al.  BH3 domains of BH3-only proteins differentially regulate Bax-mediated mitochondrial membrane permeabilization both directly and indirectly. , 2005, Molecular cell.

[29]  P. Fisher,et al.  Mechanistic aspects of mda-7/IL-24 cancer cell selectivity analysed via a bacterial fusion protein , 2004, Oncogene.

[30]  P. Dent,et al.  Inhibition of PI-3 kinase sensitizes human leukemic cells to histone deacetylase inhibitor-mediated apoptosis through p44/42 MAP kinase inactivation and abrogation of p21CIP1/WAF1 induction rather than AKT inhibition , 2003, Oncogene.

[31]  Tullio Pozzan,et al.  BAX and BAK Regulation of Endoplasmic Reticulum Ca2+: A Control Point for Apoptosis , 2003, Science.

[32]  P. Fisher,et al.  Melanoma differentiation associated gene-7, mda-7/IL-24, selectively induces growth suppression, apoptosis and radiosensitization in malignant gliomas in a p53-independent manner , 2003, Oncogene.

[33]  P. Fisher,et al.  mda-7 (IL-24) mediates selective apoptosis in human melanoma cells by inducing the coordinated overexpression of the GADD family of genes by means of p38 MAPK , 2002, Proceedings of the National Academy of Sciences of the United States of America.

[34]  R. Bataille,et al.  Antisense strategy shows that Mcl-1 rather than Bcl-2 or Bcl-x(L) is an essential survival protein of human myeloma cells. , 2002, Blood.

[35]  S. Grant,et al.  The Histone Deacetylase Inhibitor Sodium Butyrate Interacts Synergistically with Phorbol Myristate Acetate (PMA) to Induce Mitochondrial Damage and Apoptosis in Human Myeloid Leukemia Cells through a Tumor Necrosis Factor-α-Mediated Process , 2002 .

[36]  D. Spiller,et al.  Apoptosis is rapidly triggered by antisense depletion of MCL-1 in differentiating U937 cells. , 2000, Blood.

[37]  Anne Bertolotti,et al.  Dynamic interaction of BiP and ER stress transducers in the unfolded-protein response , 2000, Nature Cell Biology.

[38]  A. Fornace,et al.  Leukemic HRX Fusion Proteins Inhibit GADD34-Induced Apoptosis and Associate with the GADD34 and hSNF5/INI1 Proteins , 1999, Molecular and Cellular Biology.

[39]  Z. Su,et al.  Subtraction hybridization identifies a novel melanoma differentiation associated gene, mda-7, modulated during human melanoma differentiation, growth and progression. , 1995, Oncogene.

[40]  D. Liebermann,et al.  Sequence of MyD116 cDNA: a novel myeloid differentiation primary response gene induced by IL6. , 1990, Nucleic acids research.

[41]  P. Dent,et al.  The BH 3-only protein Bim plays a critical role in leukemia cell death triggered by concomitant inhibition of the PI 3 K / Akt and MEK / ERK 1 / 2 pathways , 2009 .

[42]  Chao Zhang,et al.  IRE 1 Signaling Affects Cell Fate During the Unfolded Protein Response , 2008 .

[43]  S. Grant,et al.  The histone deacetylase inhibitor sodium butyrate interacts synergistically with phorbol myristate acetate (PMA) to induce mitochondrial damage and apoptosis in human myeloid leukemia cells through a tumor necrosis factor-alpha-mediated process. , 2002, Experimental cell research.

[44]  Nikolaus Rajewsky,et al.  Modeling the Initiation and Progression of Human Acute Leukemia in Mice , 2022 .