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Phosphatidylinositol 3-kinase/Akt signaling mediates interleukin-6 protection against p53-induced apoptosis in M1 myeloid leukemic cells

Oncogene volume 26, pages 3041–3050 (2007)Cite this article

Abstract

M1 myeloid leukemic cells were used to dissect the molecular mechanisms of myeloid cell survival and apoptosis. A salient feature of M1 cells is that they respond to the physiological survival factor interleukin-6 (IL-6), yet lack the tumor suppressor gene p53. Functional wild-type activation of temperature-sensitive p53 protein (p53 val) at permissive temperature in M1-t-p53 cells results in rapid apoptosis, which is blocked by IL-6. How p53 induces M1 apoptosis and how IL-6 protects against p53-induced apoptosis are not fully understood. Here it is shown that p53-mediated apoptosis of M1 cells involves rapid activation of the proapoptotic Fas/CD95 death pathway, which activates caspases 8 and 10. Functional p53 also targets the mitochondria, causing upregulation of proapoptotic Bax, downregulation of prosurvival Bcl-2 and activation of caspase 9. IL-6 was found to protect against p53-induced apoptosis via activation of the PI3K/Akt survival pathway, which in turn counters both the Fas/CD95 and mitochondrial apoptotic pathways and activates the prosurvival transcription factor nuclear factor-kappaB (NF-κB). Taken together, this work supports a novel model for leukemic progression where cells that acquire the ability to produce an autocrine survival factor, such as IL-6, can bypass normal p53 surveillance function by targeting Akt, which in turn can exert effects on the regulators of apoptosis, such as the Fas/CD95 pathway, the mitochondria and NF-κB.

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Acknowledgements

This work was funded by the following grants: NIH 1 RO1 HL 70530-01 (DAL) NIH, RO1 CA081168-06 (BH).

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Authors and Affiliations

  1. Fels Institute for Cancer Research & Molecular Biology, Temple University School of Medicine, Philadelphia, PA, USA

    D L Vesely, B Hoffman & D A Liebermann

  2. Department of Biochemistry, Temple University School of Medicine, Philadelphia, PA, USA

    D L Vesely, B Hoffman & D A Liebermann

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  1. D L Vesely
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Correspondence to D A Liebermann.

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Vesely, D., Hoffman, B. & Liebermann, D. Phosphatidylinositol 3-kinase/Akt signaling mediates interleukin-6 protection against p53-induced apoptosis in M1 myeloid leukemic cells. Oncogene 26, 3041–3050 (2007). https://doi.org/10.1038/sj.onc.1210109

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