TY  - JOUR
A1  - Raab, Monika
A1  - Rak, Marcel
A1  - Tesch, Roberta
A1  - Gasimli, Khayal
A1  - Becker, Sven
A1  - Knapp, Stefan
A1  - Strebhardt, Klaus
A1  - Sanhaji, Mourad
T1  - The small-molecule inhibitor MRIA9 reveals novel insights into the cell cycle roles of SIK2 in ovarian cancer cells
T2  - Cancers
N2  - 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.
KW  - Salt inducible kinase 2 (SIK2)
KW  - the small molecule inhibitor MRIA9
KW  - spindle mispositioning
KW  - chromosomal instability
KW  - ovarian cancer
KW  - paclitaxel sensitization
Y1  - 2021
UR  - http://publikationen.ub.uni-frankfurt.de/frontdoor/index/index/docId/62458
UR  - https://nbn-resolving.org/urn:nbn:de:hebis:30:3-624587
SN  - 2072-6694
VL  - 13
IS  - 15, art. 3658
SP  - 1
EP  - 19
PB  - MDPI
CY  - Basel
ER  -