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AKT activity regulates the ability of mTOR inhibitors to prevent angiogenesis and VEGF expression in multiple myeloma cells

Oncogene volume 26, pages 2255–2262 (2007)Cite this article

Abstract

We recently demonstrated that the mammalian target of rapamycin (mTOR) inhibitor, CCI-779, curtailed the growth of a subcutaneous challenge of multiple myeloma (MM) cells in immunodeficient mice. This antitumor effect was associated with prevention of cell proliferation, induction of apoptosis and inhibition of angiogenesis. Interestingly, myeloma tumors with heightened AKT activation were particularly sensitive to a CCI-779-induced antitumor response. To investigate whether part of the differential sensitivity was due to an AKT-regulated effect on angiogenesis, we compared the effects of mTOR inhibitors against isogenic MM cell lines that only differ by their degree of AKT activity. In this model, heightened AKT activity significantly sensitized MM cells to the following inhibitory effects of mTOR inhibition: angiogenesis in vivo, vascular endothelial growth factor (VEGF) expression in vitro and in vivo and VEGF translation (but not transcription). Assessment of p70S6 kinase activity indicated that rapamycin induced comparable mTOR inhibition in both cell lines suggesting that an adverse effect on VEGF cap-dependent translation would be comparable. Internal ribosome entry site (IRES)-mediated cap-independent translation is a salvage pathway for protein expression when mTOR is inhibited, so we analyzed a possible regulatory role of AKT on VEGF IRES activity. We found that elevated AKT activity inhibited VEGF IRES function. These results support a mechanism whereby AKT prevents VEGF IRES activity in myeloma cells during mTOR inhibition resulting in a more complete abrogation of VEGF translation, and ultimately, angiogenesis.

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Acknowledgements

We thank Dr Joseph Gera for technical assistance and providing reagents. We also thank Dr Greg Goodall for providing reagents. This work is supported by research funds of the Multiple Myeloma Research Foundation, and NIH Grants K01CA111623, R01CA96920 and R01CA111448 and research funds of the Veteran's Administration.

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Authors and Affiliations

  1. Department of Medicine, UCLA, the Jonsson Comprehensive Cancer Center, Los Angeles, CA, USA

    P Frost, Y Shi, B Hoang & A Lichtenstein

  2. Department of Hematology-Oncology, West Los Angeles VA Medical Center, Los Angeles, CA, USA

    P Frost, Y Shi, B Hoang & A Lichtenstein

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  1. P Frost
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Correspondence to P Frost.

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Frost, P., Shi, Y., Hoang, B. et al. AKT activity regulates the ability of mTOR inhibitors to prevent angiogenesis and VEGF expression in multiple myeloma cells. Oncogene 26, 2255–2262 (2007). https://doi.org/10.1038/sj.onc.1210019

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