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

Fabrizio Miranda; David Mannion; Shujuan Liu; Yiyan Zheng; Lingegowda S Mangala; Clara Redondo; Sandra Herrero-Gonzalez; Ruoyan Xu; Charlotte Taylor; Donatien Fotso Chedom; Eli M Carrami; 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, Jr; Hideyuki Saya; Hwan Geun Choi; Nathanael S Gray; Roman Fischer; Benedikt M Kessler; Christopher Yau; Anil K Sood; Takeshi Motohara; Stefan Knapp; Ahmed Ashour Ahmed

doi:10.1016/j.ccell.2016.06.020

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

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

Fabrizio Miranda, David Mannion, Shujuan Liu, Yiyan Zheng, Lingegowda S Mangala, Clara Redondo, Sandra Herrero-Gonzalez, Ruoyan Xu, Charlotte Taylor, Donatien Fotso Chedom, …

Cancer cell, Vol.30(2), pp.273-289

08/08/2016

DOI: https://doi.org/10.1016/j.ccell.2016.06.020

PMID: 27478041

Abstract

Acetyl-CoA Carboxylase - metabolism

Adipocytes - enzymology

Adipocytes - metabolism

Adipocytes - pathology

AMP-Activated Protein Kinases - metabolism

Animals

Female

Heterografts

Humans

Mice

Mice, Inbred C57BL

Mice, Nude

Neoplasm Metastasis

Oncogene Protein v-akt - metabolism

Ovarian Neoplasms - enzymology

Ovarian Neoplasms - genetics

Ovarian Neoplasms - metabolism

Ovarian Neoplasms - pathology

Phosphatidylinositol 3-Kinases - metabolism

Protein Serine-Threonine Kinases - metabolism

Signal Transduction

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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Title: Salt-Inducible Kinase 2 Couples Ovarian Cancer Cell Metabolism with Survival at the Adipocyte-Rich Metastatic Niche
Creators - without role: Fabrizio Miranda - MRC Weatherall Institute of Molecular Medicine
David Mannion - MRC Weatherall Institute of Molecular Medicine
Shujuan Liu - MRC Weatherall Institute of Molecular Medicine
Yiyan Zheng - MRC Weatherall Institute of Molecular Medicine
Lingegowda S Mangala - The University of Texas MD Anderson Cancer Center
Clara Redondo - MRC Weatherall Institute of Molecular Medicine
Sandra Herrero-Gonzalez - MRC Weatherall Institute of Molecular Medicine
Ruoyan Xu - MRC Weatherall Institute of Molecular Medicine
Charlotte Taylor - MRC Weatherall Institute of Molecular Medicine
Donatien Fotso Chedom - MRC Weatherall Institute of Molecular Medicine
Eli M Carrami
Ashwag Albukhari - MRC Weatherall Institute of Molecular Medicine
Dahai Jiang - The University of Texas MD Anderson Cancer Center
Sunila Pradeep - The University of Texas MD Anderson Cancer Center
Cristian Rodriguez-Aguayo - The University of Texas MD Anderson Cancer Center
Gabriel Lopez-Berestein - The University of Texas MD Anderson Cancer Center
Eidarus Salah - Genomics England
Kamal R Abdul Azeez - University of Oxford
Jonathan M Elkins - Genomics England
Leticia Campo - University of Oxford
Kevin A Myers - University of Oxford
Daniel Klotz - MRC Weatherall Institute of Molecular Medicine
Serena Bivona - MRC Weatherall Institute of Molecular Medicine
Sunanda Dhar - Oxford University Hospitals NHS Trust
Robert C Bast, Jr - Department of Experimental Therapeutics, University of Texas M.D. Anderson Cancer Center, Houston, TX 77030, USA
Hideyuki Saya - Keio University
Hwan Geun Choi - Harvard University
Nathanael S Gray - Harvard University
Roman Fischer - University of Oxford
Benedikt M Kessler - University of Oxford
Christopher Yau - Wellcome Centre for Human Genetics
Anil K Sood - The University of Texas MD Anderson Cancer Center
Takeshi Motohara - Kumamoto University
Stefan Knapp - Genomics England
Ahmed Ashour Ahmed - MRC Weatherall Institute of Molecular Medicine
Publication Details: Cancer cell, Vol.30(2), pp.273-289
Grant note: 092809/Z/10/Z / Wellcome Trust UH3 TR000943 / NCATS NIH HHS MR/L001411/1 / Medical Research Council Cancer Research UK G0902418 / Medical Research Council 090532/Z/09/Z / Wellcome Trust
Identifiers: 9938944808331
Academic Unit: King Abdulaziz University
Language: English
Resource Type: Journal article