PARENT SESSION
1:30 PM to 3:30 PM
Tuesday, April 23, 2002
Poster Session 17 Induced Gene Expression
Room: Nevada Exhibition Center
(P22-244) The Global Response to Radiation in Prostate Adenocarcinoma C4-2 Cells.
Gong, Bendi*,1,2, Buchsbaum, Jeffrey1, Klein, Eric3, Heston, Warren2, Almasan, Alex1,2, 1 Department of Radiation Oncology, Cleveland, Ohio2 Department of Cancer Biology, Cleveland, Ohio3 Department of Urology, Cleveland, Ohio
ABSTRACT-
The response of eukaryotic cells to ionizing radiation (IR) includes cell cycle arrest, apoptosis, and DNA repair, processes which requires activation of multiple genes. Since apoptosis is deregulated in most cancers, apoptotic-modulating therapies offer an attractive opportunity for clinical therapy of many tumors, including that of the prostate. To identify genes whose expression contributes to radiation induced apoptosis of prostate cancer (CaP) cells, we used oligonucleotide microarray technology to interrogate the expression of 60,000 human genes and ESTs following ionizing radiation and kinetic response of 12,000 genes over 24 hours at ten time points. We found that 10 Gy IR caused an early G2/M, a late G1 accumulation, as well as an S-phase drop during the 48 hour period. At 6 and 24 hours, IR yielded a number of significantly up and down-regulated genes and ESTs. We focused on genes involved in G1/S and G2/M checkpoints, apoptosis, and DNA repair. Regulation of 23 of these genes was confirmed by Quantitative RT-PCR and Multiple RNase protection. Kinetic data analysis further clarified the potential role of early response, late response, and down-regulated genes in CaP following IR. The majority of down-regulated genes are cell cycle regulators, such as Cyclins, E2F, and Myc. Induced genes include the p53 target genes such as p21/waf1, DDB2, and GADD45, and apoptosis promoters such as Bax, Fas and a newly discovered cell death protein PUMA. PUMA is part of the bcl-2 family, sharing a conserved BH3 domain and is located in the mitochondria. Its role in apoptosis, as well as that of several novel EST targets is under further investigation. The total genome response to radiation is yielding new information that may direct CaP therapy. As the human genome becomes fully characterized, the data described may be applied to numerous, novel therapeutic targets. Supported by CA 81504 and CA 82858.
KEYWORDS: expression profiling, cell cycle, gene expression, apoptosis