Salt-Inducible Kinase 2 Couples Ovarian Cancer Cell Metabolism with Survival at the Adipocyte-Rich Metastatic Niche PMID: 27478041

ADC Targets in Oncology

2026-04-10

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

Cancer Cell. 2016 Aug 8;30(2):273-289. doi: 10.1016/j.ccell.2016.06.020.

Fabrizio Miranda ¹ , David Mannion ¹ , Shujuan Liu ¹ , Yiyan Zheng ¹ , Lingegowda S Mangala ² , Clara Redondo ³ , Sandra Herrero-Gonzalez ¹ , Ruoyan Xu ¹ , Charlotte Taylor ¹ , Donatien Fotso Chedom ¹ , Eli M Carrami ¹ , Ashwag Albukhari ⁴ , Dahai Jiang ² , Sunila Pradeep ⁵ , Cristian Rodriguez-Aguayo ⁶ , Gabriel Lopez-Berestein ⁶ , Eidarus Salah ⁷ , Kamal R Abdul Azeez ⁷ , Jonathan M Elkins ⁷ , Leticia Campo ⁸ , Kevin A Myers ⁸ , Daniel Klotz ¹ , Serena Bivona ¹ , Sunanda Dhar ⁹ , Robert C Bast Jr ¹⁰ , Hideyuki Saya ¹¹ , Hwan Geun Choi ¹² , Nathanael S Gray ¹² , Roman Fischer ¹³ , Benedikt M Kessler ¹³ , Christopher Yau ¹⁴ , Anil K Sood ² , Takeshi Motohara ¹⁵ , Stefan Knapp ¹⁶ , Ahmed Ashour Ahmed ¹⁷

Affiliations

1. 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.
2. Gynecologic Oncology, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, TX 77030, USA; Center for RNAi and Non-Coding RNA, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, TX 77030, USA.
3. 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; Structural Genomics Consortium, Nuffield Department of Medicine, University of Oxford, Old Road Campus Research Building, Oxford OX3 7DQ, UK.
4. 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; Biochemistry Department, Faculty of Science, King Abdulaziz University, Jeddah 21551, Saudi Arabia.
5. Gynecologic Oncology, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, TX 77030, USA.
6. Center for RNAi and Non-Coding RNA, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, TX 77030, USA; Department of Experimental Therapeutics, University of Texas M.D. Anderson Cancer Center, Houston, TX 77030, USA.
7. Structural Genomics Consortium, Nuffield Department of Medicine, University of Oxford, Old Road Campus Research Building, Oxford OX3 7DQ, UK.
8. Department of Oncology, University of Oxford, Old Road Campus Research Building, Roosevelt Drive, Oxford OX3 7DQ, UK.
9. Department of Histopathology, Oxford University Hospitals, Oxford OX3 9DU, UK.
10. Department of Experimental Therapeutics, University of Texas M.D. Anderson Cancer Center, Houston, TX 77030, USA.
11. Division of Gene Regulation, Institute for Advanced Medical Research, School of Medicine, Keio University, Tokyo 160-8582, Japan.
12. Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA 02115, USA; Department of Cancer Biology, Dana Farber Cancer Institute, Boston, MA 02215, USA.
13. Nuffield Department of Medicine, Target Discovery Institute, University of Oxford, Oxford OX3 7FZ, UK.
14. Wellcome Trust Centre for Human Genetics, NIHR Biomedical Research Centre, Roosevelt Drive, Oxford OX3 7BN, UK; Department of Statistics, University of Oxford, 1 South Parks Road, Oxford OX1 3TG, UK.
15. Department of Obstetrics and Gynecology, Faculty of Life Sciences, Kumamoto University, Kumamoto 860-8556, Japan.
16. Structural Genomics Consortium, Nuffield Department of Medicine, University of Oxford, Old Road Campus Research Building, Oxford OX3 7DQ, UK; Nuffield Department of Medicine, Target Discovery Institute, University of Oxford, Oxford OX3 7FZ, UK; Goethe-University Frankfurt, Institute for Pharmaceutical Chemistry and Buchmann Institute for Life Sciences, Riedberg Campus, 60438 Frankfurt am Main, Germany.
17. 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. Electronic address: [email protected].

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.