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; Mohammad Karaminejadranjbar; 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, Mohammad Karaminejadranjbar, 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

Research output: Contribution to journal › Article › peer-review

80 Citations (Scopus)

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.

Original language	English
Pages (from-to)	273-289
Number of pages	17
Journal	Cancer Cell
Volume	30
Issue number	2
Early online date	28 Jul 2016
DOIs	https://doi.org/10.1016/j.ccell.2016.06.020
Publication status	Published - 8 Aug 2016

Keywords

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

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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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., Karaminejadranjbar, 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. Advance online publication. https://doi.org/10.1016/j.ccell.2016.06.020

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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.",

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

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 Mohammad Karaminejadranjbar 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}",

year = "2016",

month = aug,

day = "8",

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

language = "English",

volume = "30",

pages = "273--289",

journal = "Cancer Cell",

issn = "1535-6108",

publisher = "Elsevier",

number = "2",

}

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 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

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 - Karaminejadranjbar, Mohammad

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

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.

KW - AMP-Activated Protein Kinases/metabolism

KW - Acetyl-CoA Carboxylase/metabolism

KW - Adipocytes/enzymology

KW - Animals

KW - Female

KW - Heterografts

KW - Humans

KW - Mice

KW - Mice, Inbred C57BL

KW - Mice, Nude

KW - Neoplasm Metastasis

KW - Oncogene Protein v-akt/metabolism

KW - Ovarian Neoplasms/enzymology

KW - Phosphatidylinositol 3-Kinases/metabolism

KW - Protein-Serine-Threonine Kinases/metabolism

KW - Signal Transduction

U2 - 10.1016/j.ccell.2016.06.020

DO - 10.1016/j.ccell.2016.06.020

M3 - Article

C2 - 27478041

SN - 1535-6108

VL - 30

SP - 273

EP - 289

JO - Cancer Cell

JF - Cancer Cell

IS - 2

ER -

Salt-inducible kinase 2 couples ovarian cancer cell metabolism with survival at the adipocyte-rich metastatic niche

Abstract

Keywords

UN SDGs

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