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

Oncogene. 2013 Jan 10;32(2):160-70. doi: 10.1038/onc.2012.47. Epub 2012 Feb 20.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Arachidonic Acid / metabolism*
  • Breast Neoplasms / metabolism*
  • Cell Line, Tumor
  • Cell Proliferation
  • Cell Transformation, Neoplastic / metabolism*
  • Chick Embryo
  • Cyclooxygenase 2
  • Female
  • Humans
  • Lipoxygenase / metabolism
  • MCF-7 Cells
  • Mechanistic Target of Rapamycin Complex 1
  • Mechanistic Target of Rapamycin Complex 2
  • Multiprotein Complexes / metabolism*
  • Neovascularization, Pathologic / metabolism*
  • Phosphatidylinositol 3-Kinase / metabolism
  • Phospholipases A2 / analysis
  • Proteins / metabolism*
  • RNA Interference
  • RNA, Small Interfering
  • Rats
  • Rats, Sprague-Dawley
  • Signal Transduction*
  • Sirolimus / pharmacology
  • TOR Serine-Threonine Kinases / metabolism*
  • Tuberous Sclerosis Complex 2 Protein
  • Tumor Suppressor Proteins / metabolism
  • Vascular Endothelial Growth Factor A / metabolism

Substances

  • Multiprotein Complexes
  • Proteins
  • RNA, Small Interfering
  • TSC2 protein, human
  • Tsc2 protein, rat
  • Tuberous Sclerosis Complex 2 Protein
  • Tumor Suppressor Proteins
  • VEGFA protein, human
  • Vascular Endothelial Growth Factor A
  • Arachidonic Acid
  • Lipoxygenase
  • Cyclooxygenase 2
  • TOR Serine-Threonine Kinases
  • Phosphatidylinositol 3-Kinase
  • Mechanistic Target of Rapamycin Complex 1
  • Mechanistic Target of Rapamycin Complex 2
  • Phospholipases A2
  • Sirolimus