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 i...

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Published inCancers Vol. 13; no. 15; p. 3658
Main Authors Raab, Monika, Rak, Marcel, Tesch, Roberta, Gasimli, Khayal, Becker, Sven, Knapp, Stefan, Strebhardt, Klaus, Sanhaji, Mourad
Format Journal Article
LanguageEnglish
Published Basel MDPI AG 21.07.2021
MDPI
Subjects
Adipocytes
AMP
AMP-activated protein kinase
Apoptosis
Cell cycle
Cell death
Cell division
Chemotherapy
chromosomal instability
Enzyme kinetics
Gene expression
Genomic instability
Homeostasis
Kinases
Metastases
Metastasis
Mitosis
Ovarian cancer
Paclitaxel
paclitaxel sensitization
Patients
Phosphorylation
Proteins
Salt inducible kinase 2 (SIK2)
Salt-inducible kinase
Spheroids
spindle mispositioning
the small molecule inhibitor MRIA9
Tumor cell lines
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Abstract 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.
AbstractList 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.
Simple SummaryThe current standard therapy of ovarian cancers comprises a reductive surgery followed by a combination of taxane-platinum-based primary chemotherapy. However, despite an initial positive response, patients in the advanced stage showed relapse within months or even weeks. Thus, there is a need to find combinatorial therapies that permit overcoming the paclitaxel-associated resistance in patients. Here, we found that MRIA9, a newly developed small-molecule inhibitor of the salt-inducible-kinase 2, interferes with the cell division of cancer cells. More importantly, MRIA9 increases paclitaxel efficiency in eliminating ovarian cancer cells and patient derived cancer cells by inducing apoptosis or programmed cell death. Thus, our study indicates that MRIA9 might represent a novel therapeutical tool for translational studies to overcome paclitaxel resistance in ovarian cancer.AbstractThe 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.
Author Rak, Marcel
Knapp, Stefan
Raab, Monika
Sanhaji, Mourad
Tesch, Roberta
Gasimli, Khayal
Strebhardt, Klaus
Becker, Sven
AuthorAffiliation 4 German Translational Cancer Network (DKTK), Frankfurt Cancer Institute (FCI), 60438 Frankfurt, Germany
3 Structural Genomics Consortium (SGC), Buchmann Institute for Life Sciences, Johann Wolfgang Goethe University, Max-von-Laue-Str. 15, 60438 Frankfurt, Germany
5 German Cancer Consortium (DKTK)/German Cancer Research Center, 69120 Heidelberg, Germany
1 Department of Gynecology, Medical School, Goethe University, 60590 Frankfurt, Germany; monika.raab@kgu.de (M.R.); khayal.gasimli@kgu.de (K.G.); sven.becker@kgu.de (S.B.); strebhardt@em.uni-frankfurt.de (K.S.)
2 Institute of Pharmaceutical Chemistry, Johann Wolfgang Goethe University, Max-von-Laue-Str. 9, 60438 Frankfurt, Germany; rak@pharmchem.uni-frankfurt.de (M.R.); tesch@pharmchem.uni-frankfurt.de (R.T.); knapp@pharmchem.uni-frankfurt.de (S.K.)
AuthorAffiliation_xml – name: 2 Institute of Pharmaceutical Chemistry, Johann Wolfgang Goethe University, Max-von-Laue-Str. 9, 60438 Frankfurt, Germany; rak@pharmchem.uni-frankfurt.de (M.R.); tesch@pharmchem.uni-frankfurt.de (R.T.); knapp@pharmchem.uni-frankfurt.de (S.K.)
– name: 4 German Translational Cancer Network (DKTK), Frankfurt Cancer Institute (FCI), 60438 Frankfurt, Germany
– name: 3 Structural Genomics Consortium (SGC), Buchmann Institute for Life Sciences, Johann Wolfgang Goethe University, Max-von-Laue-Str. 15, 60438 Frankfurt, Germany
– name: 1 Department of Gynecology, Medical School, Goethe University, 60590 Frankfurt, Germany; monika.raab@kgu.de (M.R.); khayal.gasimli@kgu.de (K.G.); sven.becker@kgu.de (S.B.); strebhardt@em.uni-frankfurt.de (K.S.)
– name: 5 German Cancer Consortium (DKTK)/German Cancer Research Center, 69120 Heidelberg, Germany
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Snippet 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...
Simple SummaryThe current standard therapy of ovarian cancers comprises a reductive surgery followed by a combination of taxane-platinum-based primary...
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StartPage 3658
SubjectTerms Adipocytes
AMP
AMP-activated protein kinase
Apoptosis
Cell cycle
Cell death
Cell division
Chemotherapy
chromosomal instability
Enzyme kinetics
Gene expression
Genomic instability
Homeostasis
Kinases
Metastases
Metastasis
Mitosis
Ovarian cancer
Paclitaxel
paclitaxel sensitization
Patients
Phosphorylation
Proteins
Salt inducible kinase 2 (SIK2)
Salt-inducible kinase
Spheroids
spindle mispositioning
the small molecule inhibitor MRIA9
Tumor cell lines
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Title The Small-Molecule Inhibitor MRIA9 Reveals Novel Insights into the Cell Cycle Roles of SIK2 in Ovarian Cancer Cells
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https://doaj.org/article/45776f2d692b4145913c4f7d3cd27931
Volume 13
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