The Small-Molecule Inhibitor MRIA9 Reveals Novel Insights into the Cell Cycle Roles of SIK2 in Ovarian Cancer Cells.
The Small-Molecule Inhibitor MRIA9 Reveals Novel Insights into the Cell Cycle Roles of SIK2 in Ovarian Cancer Cells.
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DOI：
10.3390/cancers13153658
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发表时间：
2021-07-21
期刊：
影响因子：
5.2
通讯作者：
Sanhaji M
中科院分区：
文献类型：
--
作者：
Raab M;Rak M;Tesch R;Gasimli K;Becker S;Knapp S;Strebhardt K;Sanhaji M
目前卵巢癌的标准治疗包括减量手术和紫杉烷-铂为主的初级化疗相结合。然而，尽管最初的反应是积极的，但晚期患者在几个月甚至几周内就复发了。因此，有必要寻找能够克服患者紫杉醇相关耐药的联合疗法。在这里，我们发现MRIA9，一种新开发的盐诱导蛋白2的小分子抑制物，干扰癌细胞的细胞分裂。更重要的是，MRIA9通过诱导细胞凋亡或程序性细胞死亡，提高了紫杉醇清除卵巢癌细胞和患者来源癌细胞的效率。因此，我们的研究表明，MRIA9可能是克服卵巢癌紫杉醇耐药的翻译研究的一种新的治疗工具。盐诱导蛋白激酶2(SIK2)是AMP活化蛋白激酶(AMPK)相关蛋白家族的成员之一，其活性与维持细胞和能量平衡的多种生物学过程有关。SIK2在几种癌症中过表达，包括卵巢癌，在卵巢癌中它促进了转移的增殖。此外，SIK2作为一种中心体激酶，已被证明调节G2/M转变，其缺失使卵巢癌对以紫杉醇为基础的化疗敏感。在这里，我们报告了使用一种新的选择性抑制剂MRIA9抑制SIK2对卵巢癌有丝分裂的影响以及与紫杉醇的协同作用。我们发现MRIA9诱导的对SIK2的抑制阻断了中心体的分离，损害了中心体的排列，并导致有丝分裂过程中纺锤体的错误定位。此外，使用MRIA9抑制SIK2增加了染色体的不稳定性，揭示了SIK2在维持基因组稳定中的作用。最后，MRIA9治疗提高了来自卵巢癌细胞系和卵巢癌患者的3D球体对紫杉醇的敏感性。我们的研究建议在卵巢癌中选择性靶向SIK2作为克服紫杉醇耐药的治疗策略。
The 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. 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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影响因子：
50.3
作者：
Ahmed AA;Lu Z;Jennings NB;Etemadmoghadam D;Capalbo L;Jacamo RO;Barbosa-Morais N;Le XF;Australian Ovarian Cancer Study Group;Vivas-Mejia P;Lopez-Berestein G;Grandjean G;Bartholomeusz G;Liao W;Andreeff M;Bowtell D;Glover DM;Sood AK;Bast RC Jr
通讯作者：
Bast RC Jr
影响因子：
4.7
作者：
Feldman, JD;Vician, L;Herschman, HR
通讯作者：
Herschman, HR
影响因子：
3.8
作者：
McShane, Lisa M.;Altman, Douglas G.;Clark, Gary M.
通讯作者：
Clark, Gary M.
影响因子：
11.2
作者：
O'Reilly, KE;Rojo, F;Rosen, N
通讯作者：
Rosen, N
影响因子：
4.6
作者：
Almada E;Tonucci FM;Hidalgo F;Ferretti A;Ibarra S;Pariani A;Vena R;Favre C;Girardini J;Kierbel A;Larocca MC
通讯作者：
Larocca MC