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Oncogenic PI3K and K-Ras stimulate de novo lipid synthesis through mTORC1 and SREBP

Oncogene volume 35, pages 1250–1260 (2016)Cite this article

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Abstract

An enhanced capacity for de novo lipid synthesis is a metabolic feature of most cancer cells that distinguishes them from their cells of origin. However, the mechanisms through which oncogenes alter lipid metabolism are poorly understood. We find that expression of oncogenic PI3K (H1047R) or K-Ras (G12V) in breast epithelial cells is sufficient to induce de novo lipogenesis, and this occurs through the convergent activation of the mechanistic target of rapamycin complex 1 (mTORC1) downstream of these common oncogenes. Oncogenic stimulation of mTORC1 signaling in this isogenic setting or a panel of eight breast cancer cell lines leads to activation of the sterol regulatory element-binding proteins (SREBP1 and SREBP2) that are required for oncogene-induced lipid synthesis. The SREBPs are also required for the growth factor-independent growth and proliferation of oncogene-expressing cells. Finally, we find that elevated mTORC1 signaling is associated with increased mRNA and protein levels of canonical SREBP targets in primary human breast cancer samples. These data suggest that the mTORC1/SREBP pathway is a major mechanism through which common oncogenic signaling events induce de novo lipid synthesis to promote aberrant growth and proliferation of cancer cells.

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Acknowledgements

This work was supported in part by NSF predoctoral fellowship DGE-1144152 (to SJHR), a postdoctoral fellowship from the LAM Foundation (to IB-S), a Sanofi Innovation Award (to BDM) and NIH Grants R01-CA181390 and P01-CA120964 (to BDM).

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  1. J L Yecies

    Present address: 2Current address: Genentech, Inc., South San Francisco, CA 94080, USA.,

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  1. Department of Genetics and Complex Diseases, Harvard T.H. Chan School of Public Health, Boston, MA, USA

    S J H Ricoult, J L Yecies, I Ben-Sahra & B D Manning

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Ricoult, S., Yecies, J., Ben-Sahra, I. et al. Oncogenic PI3K and K-Ras stimulate de novo lipid synthesis through mTORC1 and SREBP. Oncogene 35, 1250–1260 (2016). https://doi.org/10.1038/onc.2015.179

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