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

Fabrizio Miranda¹, David Mannion¹, Shujuan Liu¹, Yiyan Zheng¹, Lingegowda S Mangala², Clara Redondo³, Sandra Herrero-Gonzalez¹, Ruoyan Xu¹, Charlotte Taylor¹, Donatien Fotso Chedom¹, Eli M Carrami¹, Ashwag Albukhari⁴, Dahai Jiang², Sunila Pradeep⁵, Cristian Rodriguez-Aguayo⁶, Gabriel Lopez-Berestein⁶, Eidarus Salah⁷, Kamal R Abdul Azeez⁷, Jonathan M Elkins⁷, Leticia Campo⁸, Kevin A Myers⁸, Daniel Klotz¹, Serena Bivona¹, Sunanda Dhar⁹, Robert C Bast Jr¹⁰, Hideyuki Saya¹¹, Hwan Geun Choi¹², Nathanael S Gray¹², Roman Fischer¹³, Benedikt M Kessler¹³, Christopher Yau¹⁴, Anil K Sood², Takeshi Motohara¹⁵, Stefan Knapp¹⁶, Ahmed Ashour Ahmed¹⁷

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.

PMID: 27478041
DOI: 10.1016/j.ccell.2016.06.020

Free article

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

Fabrizio Miranda et al. Cancer Cell. 2016.

Free article

. 2016 Aug 8;30(2):273-289.

doi: 10.1016/j.ccell.2016.06.020. Epub 2016 Jul 28.

Authors

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.

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

Affiliations

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

Authors

Affiliations

Abstract

MeSH terms

Substances

Grants and funding

LinkOut - more resources

Full Text Sources

Other Literature Sources

Medical

Molecular Biology Databases

Miscellaneous