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lüll mda-7 (IL-24) Inhibits growth and enhances radiosensitivity of glioma cells in vitro via JNK signaling Yacoub A; Mitchell C; Lebedeva IV; Sarkar D; Su ZZ; McKinstry R; Gopalkrishnan RV; Grant S; Fisher PB; Dent PCancer Biol Ther 2003[Jul]; 2 (4): 347-53Despite therapeutic interventions including surgery, chemotherapy and radiotherapy, glioblastoma multiforme (GBM) has a very poor prognosis and novel therapies are required. MDA-7 (IL-24), when expressed via a recombinant replication defective adenovirus, Ad.mda-7, has profound anti-proliferative and cytotoxic effects in a variety of tumor cells, but not in non-transformed cells. The present studies examined the combined impact of Ad.mda-7 and ionizing radiation on the proliferation and survival of GBM cells. Ad.mda-7 reduced the proliferation of rodent and human glioma cells in MTT assays and in colony formation assays. The anti-proliferative effects of Admda-7 were enhanced by radiation in a greater than additive fashion. In vitro, this cellular change correlated with enhanced cell numbers in G1/G0 and G2/M phases of the cell cycle, implying Ad.mda-7 radiosensitizes tumor cells in a cell cycle-independent manner. The radiosensitizing effects were not observed in cultures of non-transformed primary astrocytes. The enhanced reduction in growth correlated with increased necrosis and DNA degradation. Ad.mda-7 enhanced p38 and ERK1/2 activity but did not alter JNK or Akt activity. Irradiation of cells expressing MDA-7 suppressed ERK1/2 activity and dramatically enhanced JNK1/2 activity without altering either Akt or p38 activity. Inhibition of JNK1/2, but not p38, signaling abolished the radiosensitizing properties of MDA-7. Inhibition of neither ERK1/2 nor PI3K signaling enhanced the anti-proliferative effects of Ad.mda-7, whereas combined inhibition of both pathways enhanced cell killing, suggesting that ERK and PI3K signaling can be protective against MDA-7 lethality.|*JNK Mitogen-Activated Protein Kinases[MESH]|*Protein Serine-Threonine Kinases[MESH]|*Signal Transduction[MESH]|Adenoviridae/genetics[MESH]|Animals[MESH]|Apoptosis/physiology/*radiation effects[MESH]|Blotting, Western[MESH]|Brain Neoplasms/metabolism/pathology/*radiotherapy[MESH]|Cell Division/drug effects/radiation effects[MESH]|Cyclin-Dependent Kinase Inhibitor p21[MESH]|Cyclins/metabolism[MESH]|Dose-Response Relationship, Radiation[MESH]|Genes, Tumor Suppressor[MESH]|Glioma/metabolism/pathology/*radiotherapy[MESH]|Glutathione Transferase/metabolism[MESH]|Interleukins/genetics/*therapeutic use[MESH]|MAP Kinase Kinase 4[MESH]|Mitogen-Activated Protein Kinase 1/metabolism[MESH]|Mitogen-Activated Protein Kinase 3[MESH]|Mitogen-Activated Protein Kinase Kinases/*metabolism[MESH]|Mitogen-Activated Protein Kinases/metabolism[MESH]|Proto-Oncogene Proteins c-akt[MESH]|Proto-Oncogene Proteins/metabolism[MESH]|Radiation, Ionizing[MESH]|Radiation-Sensitizing Agents/*therapeutic use[MESH]|Rats[MESH]|Rats, Inbred F344[MESH]|Tumor Cells, Cultured[MESH]|Tumor Suppressor Protein p53/metabolism[MESH]|p38 Mitogen-Activated Protein Kinases[MESH] |