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

Miranda F., Mannion D., Liu S., Zheng Y., Mangala LS., Redondo C., Herrero-Gonzalez S., Xu R., Taylor C., Chedom DF., Karaminejadranjbar M., Albukhari A., Jiang D., Pradeep S., Rodriguez-Aguayo C., Lopez-Berestein G., Salah E., Abdul Azeez KR., Elkins JM., Campo L., Myers KA., Klotz D., Bivona S., Dhar S., Bast RC., Saya H., Choi HG., Gray NS., Fischer R., Kessler BM., Yau C., Sood AK., Motohara T., Knapp S., Ahmed AA.

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.

DOI

10.1016/j.ccell.2016.06.020

Type

Journal

Cancer Cell

Publication Date

08/08/2016

Volume

30

Pages

273 - 289

Keywords

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

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