The small-molecule inhibitor MRIA9 reveals novel insights into the cell cycle roles of SIK2 in ovarian cancer cells

  • The activity of the Salt inducible kinase 2 (SIK2), a member of the AMP-activated protein kinase (AMPK)-related kinase family, has been linked to several biological processes that maintain cellular and energetic homeostasis. SIK2 is overexpressed in several cancers, including ovarian cancer, where it promotes the proliferation of metastases. Furthermore, as a centrosome kinase, SIK2 has been shown to regulate the G2/M transition, and its depletion sensitizes ovarian cancer to paclitaxel-based chemotherapy. Here, we report the consequences of SIK2 inhibition on mitosis and synergies with paclitaxel in ovarian cancer using a novel and selective inhibitor, MRIA9. We show that MRIA9-induced inhibition of SIK2 blocks the centrosome disjunction, impairs the centrosome alignment, and causes spindle mispositioning during mitosis. Furthermore, the inhibition of SIK2 using MRIA9 increases chromosomal instability, revealing the role of SIK2 in maintaining genomic stability. Finally, MRIA9 treatment enhances the sensitivity to paclitaxel in 3D-spheroids derived from ovarian cancer cell lines and ovarian cancer patients. Our study suggests selective targeting of SIK2 in ovarian cancer as a therapeutic strategy for overcoming paclitaxel resistance.

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Author:Monika Raab, Marcel Rak, Roberta Tesch, Khayal Gasimli, Sven BeckerGND, Stefan Knapp, Klaus StrebhardtORCiD, Mourad Sanhaji
URN:urn:nbn:de:hebis:30:3-624587
DOI:https://doi.org/10.3390/cancers13153658
ISSN:2072-6694
Parent Title (English):Cancers
Publisher:MDPI
Place of publication:Basel
Document Type:Article
Language:English
Date of Publication (online):2021/07/21
Date of first Publication:2021/07/21
Publishing Institution:Universit├Ątsbibliothek Johann Christian Senckenberg
Release Date:2021/09/06
Tag:Salt inducible kinase 2 (SIK2); chromosomal instability; ovarian cancer; paclitaxel sensitization; spindle mispositioning; the small molecule inhibitor MRIA9
Volume:13
Issue:15, art. 3658
Page Number:19
First Page:1
Last Page:19
HeBIS-PPN:487476565
Institutes:Medizin / Medizin
Dewey Decimal Classification:6 Technik, Medizin, angewandte Wissenschaften / 61 Medizin und Gesundheit / 610 Medizin und Gesundheit
Sammlungen:Universit├Ątspublikationen
Licence (German):License LogoCreative Commons - Namensnennung 4.0