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CIB1 prevents nuclear GAPDH accumulation and non-apoptotic tumor cell death via AKT and ERK signaling

Oncogene volume 32, pages 4017–4027 (2013)Cite this article

Abstract

CIB1 is a 22-kDa regulatory protein previously implicated in cell survival and proliferation. However, the mechanism by which CIB1 regulates these processes is poorly defined. Here, we report that CIB1 depletion in SK-N-SH neuroblastoma and MDA-MB-468 breast cancer cells promotes non-apoptotic, caspase-independent cell death that is not initiated by increased outer mitochondrial membrane permeability or translocation of apoptosis-inducing factor to the nucleus. Instead, cell death requires nuclear GAPDH accumulation. Furthermore, CIB1 depletion disrupts two commonly dysregulated, oncogenic pathways—PI3K/AKT and Ras/MEK/ERK, resulting in a synergistic mechanism of cell death, which was mimicked by simultaneous pharmacological inhibition of both pathways, but not either pathway alone. In defining each pathway’s contributions, we found that AKT inhibition alone maximally induced GAPDH nuclear accumulation, whereas MEK/ERK inhibition alone had no effect on GAPDH localization. Concurrent GAPDH nuclear accumulation and ERK inhibition were required, however, to induce a significant DNA damage response, which was critical to subsequent cell death. Collectively, our results indicate that CIB1 is uniquely positioned to regulate PI3K/AKT and MEK/ERK signaling and that simultaneous disruption of these pathways synergistically induces a nuclear GAPDH-dependent cell death. The mechanistic insights into cell death induced by CIB1 interference suggest novel molecular targets for cancer therapy.

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Acknowledgements

We thank members of the Parise, Cook and A Sancar laboratories, Drs Yue Xiong, Matthew Torres, and Howard Fried for critical review and suggestions. We also thank Dr Akira Sawa for generously providing GAPDH plasmids. Special thanks to Dr H Fried and Andrew McFadden for lentiviral plasmid construction. This work was funded by the postdoctoral fellowship grant HL07149T32 (CM) and 5R01HL092544 (LVP) from the NIH.

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  1. T M Leisner and C Moran: These authors contributed equally to this work.

Authors and Affiliations

  1. Department of Biochemistry and Biophysics, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA

    T M Leisner, C Moran, S P Holly & L V Parise

  2. PRA International, Raleigh, NC, USA

    C Moran

  3. Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, NC, USA

    L V Parise

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Correspondence to T M Leisner.

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Leisner, T., Moran, C., Holly, S. et al. CIB1 prevents nuclear GAPDH accumulation and non-apoptotic tumor cell death via AKT and ERK signaling. Oncogene 32, 4017–4027 (2013). https://doi.org/10.1038/onc.2012.408

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