TY - JOUR
T1 - Salt-Inducible Kinase 2 Couples Ovarian Cancer Cell Metabolism with Survival at the Adipocyte-Rich Metastatic Niche
AU - Miranda, Fabrizio
AU - Mannion, David
AU - Liu, Shujuan
AU - Zheng, Yiyan
AU - Mangala, Lingegowda S.
AU - Redondo, Clara
AU - Herrero-Gonzalez, Sandra
AU - Xu, Ruoyan
AU - Taylor, Charlotte
AU - Chedom, Donatien Fotso
AU - Carrami, Eli M.
AU - Albukhari, Ashwag
AU - Jiang, Dahai
AU - Pradeep, Sunila
AU - Rodriguez-Aguayo, Cristian
AU - Lopez-Berestein, Gabriel
AU - Salah, Eidarus
AU - Abdul Azeez, Kamal R.
AU - Elkins, Jonathan M.
AU - Campo, Leticia
AU - Myers, Kevin A.
AU - Klotz, Daniel
AU - Bivona, Serena
AU - Dhar, Sunanda
AU - Bast, Robert C.
AU - Saya, Hideyuki
AU - Choi, Hwan Geun
AU - Gray, Nathanael S.
AU - Fischer, Roman
AU - Kessler, Benedikt M.
AU - Yau, Christopher
AU - Sood, Anil K.
AU - Motohara, Takeshi
AU - Knapp, Stefan
AU - Ahmed, Ahmed Ashour
N1 - Publisher Copyright:
© 2016
PY - 2016/8/8
Y1 - 2016/8/8
N2 - 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.
AB - 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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U2 - 10.1016/j.ccell.2016.06.020
DO - 10.1016/j.ccell.2016.06.020
M3 - Article
C2 - 27478041
AN - SCOPUS:84979768766
SN - 1535-6108
VL - 30
SP - 273
EP - 289
JO - Cancer cell
JF - Cancer cell
IS - 2
ER -