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

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

  • Cancer Cell. 2016 Aug 8;30(2):273-289. doi: 10.1016/j.ccell.2016.06.020.
Fabrizio Miranda 1,  David Mannion 1,  Shujuan Liu 1,  Yiyan Zheng 1,  Lingegowda S Mangala 2,  Clara Redondo 3,  Sandra Herrero-Gonzalez 1,  Ruoyan Xu 1,  Charlotte Taylor 1,  Donatien Fotso Chedom 1,  Eli M Carrami 1,  Ashwag Albukhari 4,  Dahai Jiang 2,  Sunila Pradeep 5,  Cristian Rodriguez-Aguayo 6,  Gabriel Lopez-Berestein 6,  Eidarus Salah 7,  Kamal R Abdul Azeez 7,  Jonathan M Elkins 7,  Leticia Campo 8,  Kevin A Myers 8,  Daniel Klotz 1,  Serena Bivona 1,  Sunanda Dhar 9,  Robert C Bast Jr 10,  Hideyuki Saya 11,  Hwan Geun Choi 12,  Nathanael S Gray 12,  Roman Fischer 13,  Benedikt M Kessler 13,  Christopher Yau 14,  Anil K Sood 2,  Takeshi Motohara 15,  Stefan Knapp 16,  Ahmed Ashour Ahmed 17
Affiliations

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: [email protected].
PMID: 27478041 DOI: 10.1016/j.ccell.2016.06.020
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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