title: Salt-Inducible Kinase 2 Couples Ovarian Cancer Cell Metabolism with Survival at the Adipocyte-Rich Metastatic Niche.
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.
authors.affiliation: 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.
authors.forename: Fabrizio
authors.initials: F
authors.lastname: Miranda
authors.affiliation: 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.
authors.forename: David
authors.initials: D
authors.lastname: Mannion
authors.affiliation: 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.
authors.forename: Shujuan
authors.initials: S
authors.lastname: Liu
authors.affiliation: 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.
authors.forename: Yiyan
authors.initials: Y
authors.lastname: Zheng
authors.affiliation: 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.
authors.forename: Lingegowda S
authors.initials: LS
authors.lastname: Mangala
authors.affiliation: 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.
authors.forename: Clara
authors.initials: C
authors.lastname: Redondo
authors.affiliation: 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.
authors.forename: Sandra
authors.initials: S
authors.lastname: Herrero-Gonzalez
authors.affiliation: 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.
authors.forename: Ruoyan
authors.initials: R
authors.lastname: Xu
authors.affiliation: 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.
authors.forename: Charlotte
authors.initials: C
authors.lastname: Taylor
authors.affiliation: 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.
authors.forename: Donatien Fotso
authors.initials: DF
authors.lastname: Chedom
authors.affiliation: 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.
authors.forename: Eli M
authors.initials: EM
authors.lastname: Carrami
authors.affiliation: 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.
authors.forename: Ashwag
authors.initials: A
authors.lastname: Albukhari
authors.affiliation: 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.
authors.forename: Dahai
authors.initials: D
authors.lastname: Jiang
authors.affiliation: Gynecologic Oncology, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, TX 77030, USA.
authors.forename: Sunila
authors.initials: S
authors.lastname: Pradeep
authors.affiliation: 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.
authors.forename: Cristian
authors.initials: C
authors.lastname: Rodriguez-Aguayo
authors.affiliation: 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.
authors.forename: Gabriel
authors.initials: G
authors.lastname: Lopez-Berestein
authors.affiliation: Structural Genomics Consortium, Nuffield Department of Medicine, University of Oxford, Old Road Campus Research Building, Oxford OX3 7DQ, UK.
authors.forename: Eidarus
authors.initials: E
authors.lastname: Salah
authors.affiliation: Structural Genomics Consortium, Nuffield Department of Medicine, University of Oxford, Old Road Campus Research Building, Oxford OX3 7DQ, UK.
authors.forename: Kamal R
authors.initials: KR
authors.lastname: Abdul Azeez
authors.affiliation: Structural Genomics Consortium, Nuffield Department of Medicine, University of Oxford, Old Road Campus Research Building, Oxford OX3 7DQ, UK.
authors.forename: Jonathan M
authors.initials: JM
authors.lastname: Elkins
authors.affiliation: Department of Oncology, University of Oxford, Old Road Campus Research Building, Roosevelt Drive, Oxford OX3 7DQ, UK.
authors.forename: Leticia
authors.initials: L
authors.lastname: Campo
authors.affiliation: Department of Oncology, University of Oxford, Old Road Campus Research Building, Roosevelt Drive, Oxford OX3 7DQ, UK.
authors.forename: Kevin A
authors.initials: KA
authors.lastname: Myers
authors.affiliation: 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.
authors.forename: Daniel
authors.initials: D
authors.lastname: Klotz
authors.affiliation: 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.
authors.forename: Serena
authors.initials: S
authors.lastname: Bivona
authors.affiliation: Department of Histopathology, Oxford University Hospitals, Oxford OX3 9DU, UK.
authors.forename: Sunanda
authors.initials: S
authors.lastname: Dhar
authors.affiliation: Department of Experimental Therapeutics, University of Texas M.D. Anderson Cancer Center, Houston, TX 77030, USA.
authors.forename: Robert C
authors.initials: RC
authors.lastname: Bast
authors.affiliation: Division of Gene Regulation, Institute for Advanced Medical Research, School of Medicine, Keio University, Tokyo 160-8582, Japan.
authors.forename: Hideyuki
authors.initials: H
authors.lastname: Saya
authors.affiliation: 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.
authors.forename: Hwan Geun
authors.initials: HG
authors.lastname: Choi
authors.affiliation: 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.
authors.forename: Nathanael S
authors.initials: NS
authors.lastname: Gray
authors.affiliation: Nuffield Department of Medicine, Target Discovery Institute, University of Oxford, Oxford OX3 7FZ, UK.
authors.forename: Roman
authors.initials: R
authors.lastname: Fischer
authors.affiliation: Nuffield Department of Medicine, Target Discovery Institute, University of Oxford, Oxford OX3 7FZ, UK.
authors.forename: Benedikt M
authors.initials: BM
authors.lastname: Kessler
authors.affiliation: 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.
authors.forename: Christopher
authors.initials: C
authors.lastname: Yau
authors.affiliation: 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.
authors.forename: Anil K
authors.initials: AK
authors.lastname: Sood
authors.affiliation: Department of Obstetrics and Gynecology, Faculty of Life Sciences, Kumamoto University, Kumamoto 860-8556, Japan.
authors.forename: Takeshi
authors.initials: T
authors.lastname: Motohara
authors.affiliation: 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.
authors.forename: Stefan
authors.initials: S
authors.lastname: Knapp
authors.affiliation: 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.
authors.forename: Ahmed Ashour
authors.initials: AA
authors.lastname: Ahmed
mesh_terms: D055372:AMP-Activated Protein Kinases / Q000378:metabolism; D000103:Acetyl-CoA Carboxylase / Q000378:metabolism; D017667:Adipocytes / Q000201:enzymology / Q000378:metabolism / Q000473:pathology; D000818:Animals; D005260:Female; D064593:Heterografts; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D008819:Mice, Nude; D009362:Neoplasm Metastasis; D051058:Oncogene Protein v-akt / Q000378:metabolism; D010051:Ovarian Neoplasms / Q000201:enzymology / Q000235:genetics* / Q000378:metabolism* / Q000473:pathology; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D015398:Signal Transduction
chemical_list: D055372:AMP-Activated Protein Kinases; D000103:Acetyl-CoA Carboxylase; D051058:Oncogene Protein v-akt; D019869:Phosphatidylinositol 3-Kinases; D017346:Protein Serine-Threonine Kinases; C551842:salt-inducible kinase-2, human