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; 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

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 CampoKevin A. Myers, Daniel Klotz, Serena Bivona, Sunanda Dhar, Robert C. Bast, 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

先端医科学研究所(遺伝子)

研究成果: Article › 査読

109 被引用数 (Scopus)

抄録

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.

本文言語	English
ページ（範囲）	273-289
ページ数	17
ジャーナル	Cancer Cell
巻	30
号	2
DOI	https://doi.org/10.1016/j.ccell.2016.06.020
出版ステータス	Published - 2016 8月 8

ASJC Scopus subject areas

腫瘍学
癌研究

UN SDG

この成果は、次の持続可能な開発目標に貢献しています

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10.1016/j.ccell.2016.06.020

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Miranda, F., Mannion, D., Liu, S., Zheng, Y., Mangala, L. S., Redondo, C., Herrero-Gonzalez, S., Xu, R., Taylor, C., Chedom, D. F., Carrami, E. M., Albukhari, A., Jiang, D., Pradeep, S., Rodriguez-Aguayo, C., Lopez-Berestein, G., Salah, E., Abdul Azeez, K. R., Elkins, J. M., ... Ahmed, A. A. (2016). Salt-Inducible Kinase 2 Couples Ovarian Cancer Cell Metabolism with Survival at the Adipocyte-Rich Metastatic Niche. Cancer Cell, 30(2), 273-289. https://doi.org/10.1016/j.ccell.2016.06.020

Miranda, F, Mannion, D, Liu, S, Zheng, Y, Mangala, LS, Redondo, C, Herrero-Gonzalez, S, Xu, R, Taylor, C, Chedom, DF, Carrami, EM, 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 2016, 'Salt-Inducible Kinase 2 Couples Ovarian Cancer Cell Metabolism with Survival at the Adipocyte-Rich Metastatic Niche', Cancer Cell, vol. 30, no. 2, pp. 273-289. https://doi.org/10.1016/j.ccell.2016.06.020

@article{44e9e198e13b478a8c7ca70b9e533457,

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

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.",

author = "Fabrizio Miranda and David Mannion and Shujuan Liu and Yiyan Zheng and Mangala, {Lingegowda S.} and Clara Redondo and Sandra Herrero-Gonzalez and Ruoyan Xu and Charlotte Taylor and Chedom, {Donatien Fotso} and Carrami, {Eli M.} and Ashwag Albukhari and Dahai Jiang and Sunila Pradeep and Cristian Rodriguez-Aguayo and Gabriel Lopez-Berestein and Eidarus Salah and {Abdul Azeez}, {Kamal R.} and Elkins, {Jonathan M.} and Leticia Campo and Myers, {Kevin A.} and Daniel Klotz and Serena Bivona and Sunanda Dhar and Bast, {Robert C.} and Hideyuki Saya and Choi, {Hwan Geun} and Gray, {Nathanael S.} and Roman Fischer and Kessler, {Benedikt M.} and Christopher Yau and Sood, {Anil K.} and Takeshi Motohara and Stefan Knapp and Ahmed, {Ahmed Ashour}",

note = "Funding Information: We thank the Gynecological Oncology Multidisciplinary Team at Oxford for help in recruiting patients, the Oxford Center for Histopathology Research for their technical work, and Fulvio Miranda, Karl Morten, and Matteo Morotti for helpful discussions. This work was funded by the Medical Research Council , Ovarian Cancer Action , Oxford Biomedical Research Center , the National Institute for Health Research , Cancer Research UK , Experimental Cancer Medicine Center , Helen Clarke Fund , Target Ovarian Cancer, NIH ( UH3TR000943 , P50 CA083639 ), and RGK Foundation . C.Y. acknowledges the support of an MRC New Investigator Research Grant (Ref. No. MR/L001411/1 ) and the Wellcome Trust Core Award Grant Number 090532/Z/09/Z . S.K. and C.R. are supported by the SGC , a registered charity (number 1097737 ) that receives funds from AbbVie , Bayer Pharma AG , Boehringer Ingelheim , the Canada Foundation for Innovation , Genome Canada , GlaxoSmithKline , Janssen , Lilly Canada , the Novartis Research Foundation , the Ontario Ministry of Economic Development and Innovation , Pfizer , Takeda , and the Wellcome Trust [ 092809/Z/10/Z ]. Publisher Copyright: {\textcopyright} 2016",

year = "2016",

month = aug,

day = "8",

doi = "10.1016/j.ccell.2016.06.020",

language = "English",

volume = "30",

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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 - Funding Information: We thank the Gynecological Oncology Multidisciplinary Team at Oxford for help in recruiting patients, the Oxford Center for Histopathology Research for their technical work, and Fulvio Miranda, Karl Morten, and Matteo Morotti for helpful discussions. This work was funded by the Medical Research Council , Ovarian Cancer Action , Oxford Biomedical Research Center , the National Institute for Health Research , Cancer Research UK , Experimental Cancer Medicine Center , Helen Clarke Fund , Target Ovarian Cancer, NIH ( UH3TR000943 , P50 CA083639 ), and RGK Foundation . C.Y. acknowledges the support of an MRC New Investigator Research Grant (Ref. No. MR/L001411/1 ) and the Wellcome Trust Core Award Grant Number 090532/Z/09/Z . S.K. and C.R. are supported by the SGC , a registered charity (number 1097737 ) that receives funds from AbbVie , Bayer Pharma AG , Boehringer Ingelheim , the Canada Foundation for Innovation , Genome Canada , GlaxoSmithKline , Janssen , Lilly Canada , the Novartis Research Foundation , the Ontario Ministry of Economic Development and Innovation , Pfizer , Takeda , and the Wellcome Trust [ 092809/Z/10/Z ]. 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

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AN - SCOPUS:84979768766

SN - 1535-6108

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JO - Cancer Cell

JF - Cancer Cell

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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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ASJC Scopus subject areas

UN SDG

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