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Induction of prosurvival molecules by apoptotic stimuli: involvement of FOXO3a and ROS

Oncogene volume 24, pages 2020–2031 (2005)Cite this article

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-XL 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.

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Acknowledgements

We thank R DePinho for FOXO3a+/+ and FOXO3a−/− MEFs, Biomide Corp. for BMD188, K Claypool for flow analysis, M Raff for advice and critically reading the manuscript, and the Tang lab for support. This work was supported, in part, by NIH Grants CA90297 and AG023374, ACS Grant RSG MGO-105961, DoD Grant DAMD17-03-1-0137, and NIEHS Center Grant 5 P30 ES07784 (all to DGT), and DoD Postdoctoral Fellowships DAMD17-03-1-0146 (J-WL) and DAMD17-02-1-0083 (DC).

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Authors and Affiliations

  1. Department of Carcinogenesis, the University of Texas MD Anderson Cancer Center, Science Park-Research Division 1C, Smithville, TX, 78957, USA

    Jun-Wei Liu, Dhyan Chandra, Michael D Rudd, Andrew P Butler & Dean G Tang

  2. Ambion, Inc., 2130 Woodward, Austin, TX, 78744, USA

    Vincent Pallotta & David Brown

  3. Department of Pulmonary Diseases, University Medical Center, 3584 CX, Utrecht, The Netherlands

    Paul J Coffer

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  1. Jun-Wei Liu
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Correspondence to Dean G Tang.

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Liu, JW., Chandra, D., Rudd, M. et al. Induction of prosurvival molecules by apoptotic stimuli: involvement of FOXO3a and ROS. Oncogene 24, 2020–2031 (2005). https://doi.org/10.1038/sj.onc.1208385

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