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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.

Original publication

DOI

10.1016/j.ccell.2016.06.020

Type

Journal article

Journal

Cancer cell

Publication Date

08/2016

Volume

30

Pages

273 - 289

Addresses

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.

Keywords

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