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Critical role of arachidonic acid-activated mTOR signaling in breast carcinogenesis and angiogenesis

Oncogene volume 32, pages 160–170 (2013)Cite this article

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Abstract

The mammalian target of rapamycin (mTOR) signaling pathway is upregulated in the pathogenesis of many cancers. Arachidonic acid (AA) and its metabolites play critical role in the development of breast cancer, but the mechanisms through which AA promotes mammary tumorigenesis and progression are poorly understood. We found that the levels of AA and cytosolic phospholipase A2 (cPLA2) strongly correlated with the signaling activity of mTORC1 and mTORC2 as well as the expression levels of vascular epithelial growth factor (VEGF) in human breast tumor tissues. In cultured breast cancer cells, AA effectively activated both mTOR complex 1 (mTORC1) and mTORC2. Interestingly, AA-stimulated mTORC1 activation was independent of amino acids, phosphatidylinositol 3-kinase (PI3-K) and tuberous sclerosis complex 2 (TSC2), which suggests a novel mechanism for mTORC1 activation. Further studies revealed that AA stimulated mTORC1 activity through destabilization of mTOR–raptor association in ras homolog enriched in brain (Rheb)-dependent mechanism. Moreover, we showed that AA-stimulated cell proliferation and angiogenesis required mTOR activity and that the effect of AA was mediated by lipoxygenase (LOX) but not cyclooxygenase-2 (COX-2). In animal models, AA-enhanced incidences of rat mammary tumorigenesis, tumor weights and angiogenesis were inhibited by rapamycin. Our findings suggest that AA is an effective intracellular stimulus of mTOR and that AA-activated mTOR plays critical roles in angiogenesis and tumorigenesis of breast cancer.

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Acknowledgements

We greatly appreciate the gift of TSC2+/+ and TSC2−/− MEFs from Dr David J Kwiatkowski (Brigham and Women's Hospital, Boston, MA, USA). This work was supported by The State Key Development Program for Basic Research of China (No. 2009CB 918904), National Natural Sciences Foundation of China (30870955, 91029727, 30900555) and Program for New Century Excellent Talents in University (NCET-08-0646).

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  1. Z-H Wen, Y-C Su and P-L Lai: These authors contributed equally to this work

Authors and Affiliations

  1. Department of Cell Biology, School of Basic Medical Sciences, Southern Medical University, Guangzhou, China

    Z-H Wen, Y-C Su, P-L Lai, Y Zhang, Y-F Xu, C-H Jia, J Lin, S Xu, L Wang, X-K Wang, A-L Liu & X-C Bai

  2. Center of Metabolic Disease Research, Nanjing Medical University, Nanjing, China

    A Zhao & Y-F Dai

  3. Breast Center, Nanfang Hospital, Southern Medical University, Guangzhou, China

    G-Y Yao

  4. Department of Pharmacology and Chemical Biology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA

    Y Jiang

  5. State Key Laboratory of Reproductive Medicine, Nanjing Medical University, Nanjing, China

    Y-F Dai

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Wen, ZH., Su, YC., Lai, PL. et al. Critical role of arachidonic acid-activated mTOR signaling in breast carcinogenesis and angiogenesis. Oncogene 32, 160–170 (2013). https://doi.org/10.1038/onc.2012.47

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