Salt-inducible kinase 2 couples ovarian cancer cell metabolism with survival at the adipocyte-rich metastatic niche

Research output: Contribution to journalArticle

Authors

  • Fabrizio Miranda
  • David Mannion
  • Shujuan Liu
  • Yiyan Zheng
  • Lingegowda S Mangala
  • Clara Redondo
  • Sandra Herrero-Gonzalez
  • Ruoyan Xu
  • Charlotte Taylor
  • Donatien Fotso Chedom
  • Mohammad Karaminejadranjbar
  • Ashwag Albukhari
  • Dahai Jiang
  • Sunila Pradeep
  • Cristian Rodriguez-Aguayo
  • Gabriel Lopez-Berestein
  • Eidarus Salah
  • Kamal R Abdul Azeez
  • Jonathan M Elkins
  • Leticia Campo
  • Kevin A Myers
  • Daniel Klotz
  • Serena Bivona
  • Sunanda Dhar
  • Robert C Bast
  • Hideyuki Saya
  • Hwan Geun Choi
  • Nathanael S Gray
  • Roman Fischer
  • Benedikt M Kessler
  • Anil K Sood
  • Takeshi Motohara
  • Stefan Knapp
  • Ahmed Ashour Ahmed

Colleges, School and Institutes

External organisations

  • 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.
  • 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.
  • 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.
  • 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.
  • 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; Department of Experimental Therapeutics, University of Texas M.D. Anderson Cancer Center, Houston, TX 77030, USA.
  • Structural Genomics Consortium, Nuffield Department of Medicine, University of Oxford, Old Road Campus Research Building, Oxford OX3 7DQ, UK.
  • Department of Oncology, Old Road Campus Research Building, University of Oxford, Roosevelt Drive, Oxford, OX3 7DQ, UK.
  • Department of Histopathology, Oxford University Hospitals, Oxford OX3 9DU, UK.
  • Department of Experimental Therapeutics, University of Texas M.D. Anderson Cancer Center, Houston, TX 77030, USA.
  • Division of Gene Regulation, Institute for Advanced Medical Research, School of Medicine, Keio University, Tokyo 160-8582, Japan.
  • 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.
  • Nuffield Department of Medicine, Target Discovery Institute, University of Oxford, Oxford OX3 7FZ, UK.
  • Department of Obstetrics and Gynecology, Faculty of Life Sciences, Kumamoto University, Kumamoto 860-8556, Japan.
  • 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.
  • 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.

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.

Details

Original languageEnglish
Pages (from-to)273-289
Number of pages17
JournalCancer Cell
Volume30
Issue number2
Early online date28 Jul 2016
Publication statusPublished - 8 Aug 2016

Keywords

  • AMP-Activated Protein Kinases/metabolism, Acetyl-CoA Carboxylase/metabolism, Adipocytes/enzymology, Animals, Female, Heterografts, Humans, Mice, Mice, Inbred C57BL, Mice, Nude, Neoplasm Metastasis, Oncogene Protein v-akt/metabolism, Ovarian Neoplasms/enzymology, Phosphatidylinositol 3-Kinases/metabolism, Protein-Serine-Threonine Kinases/metabolism, Signal Transduction