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The role of AKT isoforms in glioblastoma: AKT3 delays tumor progression

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Abstract

The growth factor receptor/PI3K/AKT pathway is an important drug target in many cancers including Glioblastoma. AKT, a key node in the pathway, has 3 isoforms, AKT1, AKT2 and AKT3. Here we investigate their role in GBM. We find each activated, ser473 phosphorylated isoform is present in some GBMs but expression patterns vary. There is a direct relationship between human GBM patient outcome and both AKT1 and AKT2 mRNA levels, but an inverse relationship with AKT3 mRNA. Furthermore, AKT3 mRNA levels were high in a less aggressive GBM subtype. Overexpressing AKT3 improves survival in a rodent model of GBM and decreases colony forming efficiency, but not growth rate, in glioma cells. Silencing AKT3 slows cell cycle progression in one cell line and increases apoptosis in another. Our studies of AKT3 substrates indicate (1) silencing both AKT2 and AKT3 reduces GSK3 phosphorylation (2) only AKT2 silencing reduces S6 phosphorylation. Since S6 phosphorylation is a marker of mTORC1 activity this indicates that AKT2 activates mTORC1, but AKT3 does not. Our results indicate AKT isoforms have different roles and downstream substrates in GBM. Unexpectedly, they indicate AKT3 delays tumor progression. Therefore strategies that inhibit AKT3 may be unhelpful in some GBM patients.

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Acknowledgments

This work was supported by KO1 NS064952 from the National Institutes of Health to AMJ, by 1R21EB020237 from the National Institutes of Health and an award from the Bruce Halle foundation to BGF and Barrow Neurological Foundation awards to AMJ and BGF.

Funding

This study was funded by the National Institute of Neurological Disorders and Stroke at the National Institutes of Health (K01 NS064952 to A.J.); by the National Institute of Biomedical Imaging and Bioengineering at the National Institutes of Health (R21 EB020237 to BGF); and by the Barrow Neurological Foundation and Diane and Bruce Halle Fund (B.G.F. and A.J.). The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

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  1. St. Josephs Hospital and Medical Center, Downtown campus, 445 N 5th Street, Suite 110, Phoenix, AZ, 85004, USA

    Anna Joy, Manisha Kapoor, Joseph Georges, Lacy Butler, Yongchang Chang, Chaokun Li, Acacia Crouch, James Hepler & Max Marty

  2. University of California at San Francisco, San Francisco, CA, USA

    Ivan Smirnov

  3. Department of Neurosurgery, Kanazawa University, Kanazawa, Ishikawa, Japan

    Mitsitoshi Nakada

  4. Department of Neurology, University of Arizona College of Medicine, 550 E. Van Buren St, Phoenix, AZ, 85004, USA

    Burt G. Feuerstein

  5. 318 E Kaler, Phoenix, AZ, 85020, USA

    Anna Joy

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Supplemental Fig S1

AKT3V1 is the predominant alternately spliced mRNA in GBM cell lines. (a) Schematic illustration of the domain structure of AKT3V1 and AKT3V2. (b) QRT-PCR analysis of AKT3V1 and AKT3V2 mRNA in GBM cell lines. (TIF 718 KB)

Supplemental Fig S2

Effect of silencing each AKT isoform on flow cytometric analysis of DNA content in PI stained glioma cells. (a) U87 and (b) U251 cells were incubated for 3 days after exposure to the specified AKT isoform siRNA then the histogram of count number vs PI fluorescence obtained. (a) % cells in each phase of the cell cycle was determined using FCS express. Percent cells with DNA content greater than G2/M in U87 cells is indicated. (b) Percent U251 cells in subG0 peak is indicated. (TIF 380 KB)

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Joy, A., Kapoor, M., Georges, J. et al. The role of AKT isoforms in glioblastoma: AKT3 delays tumor progression. J Neurooncol 130, 43–52 (2016). https://doi.org/10.1007/s11060-016-2220-z

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