1. Induction of prosurvival molecules by apoptotic stimuli: involvement of FOXO3a and ROS.
- Author
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Liu JW, Chandra D, Rudd MD, Butler AP, Pallotta V, Brown D, Coffer PJ, and Tang DG
- Subjects
- Apoptosis drug effects, Breast Neoplasms, Cell Line, Tumor, Cell Survival, Female, Forkhead Box Protein O1, Forkhead Transcription Factors, Gene Expression Regulation, Neoplastic, Humans, Male, Models, Biological, Prostatic Neoplasms, Proto-Oncogene Proteins c-bcl-2 genetics, RNA, Small Interfering genetics, Reverse Transcriptase Polymerase Chain Reaction, Transcription, Genetic, Transcriptional Activation, bcl-X Protein, Apoptosis physiology, DNA-Binding Proteins metabolism, Reactive Oxygen Species metabolism, Transcription Factors metabolism
- Abstract
Most cancer therapeutics fails to eradicate cancer because cancer cells rapidly develop resistance to its proapoptotic effects. The underlying mechanisms remain incompletely understood. Here we show that three representative apoptotic stimuli, that is, serum starvation, a mitochondrial toxin, and a DNA-damaging agent (etoposide), rapidly induce several distinct classes of prosurvival molecules, in particular, Bcl-2/Bcl-X(L) and superoxide dismutase (SOD; including both MnSOD and Cu/ZnSOD). At the population level, the induction of these prosurvival molecules occurs prior to or concomitant with the induction of proapoptotic molecules such as Bim and Bak. Blocking the induction using siRNAs of the prosurvival or proapoptotic molecules facilitates or inhibits apoptosis, respectively. One master transcription factor, FOXO3a, is involved in the transcriptional activation of some of these prosurvival (e.g., MnSOD) and proapoptotic (e.g., Bim) molecules. Interestingly, in all three apoptotic systems, FOXO3a itself is also upregulated at the transcriptional level. Mechanistic studies indicate that reactive oxygen species (ROS) are rapidly induced upon apoptotic stimulation and that ROS inhibitors/scavengers block the induction of FOXO3a, MnSOD, and Bim. Finally, we show that apoptotic stimuli also upregulate prosurvival molecules in normal diploid human fibroblasts and at subapoptotic concentrations. Taken together, these results suggest that various apoptotic inducers may rapidly mobilize prosurvival mechanisms through ROS-activated master transcription factors such as FOXO3a. The results imply that effective anticancer therapeutics may need to combine both apoptosis-inducing and survival-suppressing strategies.
- Published
- 2005
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