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      Salt-Inducible Kinase 2 Couples Ovarian Cancer Cell Metabolism with Survival at the Adipocyte-Rich Metastatic Niche.

      1 , 1 , 1 , 1 , 2 , 3 , 1 , 1 , 1 , 1 , 1 , 4 , 2 , 5 , 6 , 6 , 7 , 7 , 7 , 8 , 8 , 1 , 1 , 9 , 10 , 11 , 12 , 12 , 13 , 13 , 14 , 2 , 15 , 16 , 17
      Cancer cell
      Elsevier BV

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          Abstract

          The adipocyte-rich microenvironment forms a niche for ovarian cancer metastasis, but the mechanisms driving this process are incompletely understood. Here we show that salt-inducible kinase 2 (SIK2) is overexpressed in adipocyte-rich metastatic deposits compared with ovarian primary lesions. Overexpression of SIK2 in ovarian cancer cells promotes abdominal metastasis while SIK2 depletion prevents metastasis in vivo. Importantly, adipocytes induce calcium-dependent activation and autophosphorylation of SIK2. Activated SIK2 plays a dual role in augmenting AMPK-induced phosphorylation of acetyl-CoA carboxylase and in activating the PI3K/AKT pathway through p85α-S154 phosphorylation. These findings identify SIK2 at the apex of the adipocyte-induced signaling cascades in cancer cells and make a compelling case for targeting SIK2 for therapy in ovarian cancer.

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          Author and article information

          Journal
          Cancer Cell
          Cancer cell
          Elsevier BV
          1878-3686
          1535-6108
          Aug 08 2016
          : 30
          : 2
          Affiliations
          [1 ] Ovarian Cancer Cell Laboratory, Weatherall Institute of Molecular Medicine, University of Oxford, Headington, Oxford OX3 9DS, UK; Nuffield Department of Obstetrics and Gynaecology, University of Oxford, Women's Centre, John Radcliffe Hospital, Oxford OX3 9DU, UK.
          [2 ] Gynecologic Oncology, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, TX 77030, USA; Center for RNAi and Non-Coding RNA, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, TX 77030, USA.
          [3 ] Ovarian Cancer Cell Laboratory, Weatherall Institute of Molecular Medicine, University of Oxford, Headington, Oxford OX3 9DS, UK; Nuffield Department of Obstetrics and Gynaecology, University of Oxford, Women's Centre, John Radcliffe Hospital, Oxford OX3 9DU, UK; Structural Genomics Consortium, Nuffield Department of Medicine, University of Oxford, Old Road Campus Research Building, Oxford OX3 7DQ, UK.
          [4 ] Ovarian Cancer Cell Laboratory, Weatherall Institute of Molecular Medicine, University of Oxford, Headington, Oxford OX3 9DS, UK; Nuffield Department of Obstetrics and Gynaecology, University of Oxford, Women's Centre, John Radcliffe Hospital, Oxford OX3 9DU, UK; Biochemistry Department, Faculty of Science, King Abdulaziz University, Jeddah 21551, Saudi Arabia.
          [5 ] Gynecologic Oncology, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, TX 77030, USA.
          [6 ] Center for RNAi and Non-Coding RNA, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, TX 77030, USA; Department of Experimental Therapeutics, University of Texas M.D. Anderson Cancer Center, Houston, TX 77030, USA.
          [7 ] Structural Genomics Consortium, Nuffield Department of Medicine, University of Oxford, Old Road Campus Research Building, Oxford OX3 7DQ, UK.
          [8 ] Department of Oncology, University of Oxford, Old Road Campus Research Building, Roosevelt Drive, Oxford OX3 7DQ, UK.
          [9 ] Department of Histopathology, Oxford University Hospitals, Oxford OX3 9DU, UK.
          [10 ] Department of Experimental Therapeutics, University of Texas M.D. Anderson Cancer Center, Houston, TX 77030, USA.
          [11 ] Division of Gene Regulation, Institute for Advanced Medical Research, School of Medicine, Keio University, Tokyo 160-8582, Japan.
          [12 ] Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA 02115, USA; Department of Cancer Biology, Dana Farber Cancer Institute, Boston, MA 02215, USA.
          [13 ] Nuffield Department of Medicine, Target Discovery Institute, University of Oxford, Oxford OX3 7FZ, UK.
          [14 ] Wellcome Trust Centre for Human Genetics, NIHR Biomedical Research Centre, Roosevelt Drive, Oxford OX3 7BN, UK; Department of Statistics, University of Oxford, 1 South Parks Road, Oxford OX1 3TG, UK.
          [15 ] Department of Obstetrics and Gynecology, Faculty of Life Sciences, Kumamoto University, Kumamoto 860-8556, Japan.
          [16 ] Structural Genomics Consortium, Nuffield Department of Medicine, University of Oxford, Old Road Campus Research Building, Oxford OX3 7DQ, UK; Nuffield Department of Medicine, Target Discovery Institute, University of Oxford, Oxford OX3 7FZ, UK; Goethe-University Frankfurt, Institute for Pharmaceutical Chemistry and Buchmann Institute for Life Sciences, Riedberg Campus, 60438 Frankfurt am Main, Germany.
          [17 ] Ovarian Cancer Cell Laboratory, Weatherall Institute of Molecular Medicine, University of Oxford, Headington, Oxford OX3 9DS, UK; Nuffield Department of Obstetrics and Gynaecology, University of Oxford, Women's Centre, John Radcliffe Hospital, Oxford OX3 9DU, UK. Electronic address: ahmed.ahmed@obs-gyn.ox.ac.uk.
          Article
          S1535-6108(16)30280-X
          10.1016/j.ccell.2016.06.020
          27478041
          028de4f9-428b-4ddc-b5df-adf503ca98f9
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