Investigating cytokinesis failure as a strategy in cancer therapy

McKenzie, Callum; D’Avino, Pier Paolo

doi:10.18632/oncotarget.13556

Cited by 29 publications

(41 citation statements)

References 55 publications

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“…In addition, Rho-associated protein kinase serves an essential role in the metastasis and proliferation of breast cancer and hepatocellular carcinoma (31,32). The knockdown of CIT directly inhibits the proliferation of breast cancer and hepatocellular carcinoma cells (33,34). Since a previous study determined that CIT is an essential kinase that targets Rho-associated kinases (including ROCK and ROK) (27), it seems likely that CIT serves an important role in these cancers by interacting with Rho signaling.…”

Section: Discussionmentioning

confidence: 99%

High expression of citron kinase predicts poor prognosis of prostate cancer

et al. 2020

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Citron kinase (CIT) is a Rho-effector protein kinase that is associated with several types of cancer. However, the role of CIT in prostate cancer (PCa) is unclear. The current study utilized microarray data obtained from The Cancer Genome Atlas, which was analyzed via Biometric Research Program array tools. Additionally, reverse transcription-quantitative (RT-q)PCR was performed to compare the mRNA expression of CIT in PCa tissue and in benign prostatic hyperplasia. The protein expression of CIT was detected in a consecutive cohort via immunochemistry and CIT was screened as a potential oncogene in PCa. The results of RT-qPCR demonstrated that the mRNA expression of CIT was increased in PCa tissues. Furthermore, immunochemistry revealed that CIT protein expression was positively associated with age at diagnosis, Gleason grade, serum PSA, clinical T stage, risk group, lymph node invasion and metastasis. When compared with the low expression group, patients with a high CIT expression exhibited shorter survival rates, cancer specific mortalities (CSM) and biochemical recurrence (BCR). In addition, multivariate analysis revealed that CIT was a potential predictor of CSM and BCR. The results revealed that CIT is overexpressed during the malignant progression of PCa and may be a predictor of a poor patient prognosis.

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Section: Discussionmentioning

confidence: 99%

High expression of citron kinase predicts poor prognosis of prostate cancer

et al. 2020

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“…Citron kinase (CIT-K) is a contractile ring component that acts as a major midbody organizer by interacting with several midbody components and maintaining their orderly arrangement 9,10 . As a first step towards the characterization of the midbody interactome, we used a human HeLa cell line stably expressing CIT-K tagged with GFP 11 to identify the CIT-K interactomes at different cell cycle stages -S phase, metaphase and telophase -by AP-MS ( Fig. 1a-b and Supplementary Data S1).…”

Section: Citron Kinase a Key Midbody Organizer Interacts With Many mentioning

confidence: 99%

The midbody interactome reveals new unexpected roles for PP1 phosphatases in cytokinesis

Capalbo

Bassi

Geymonat

et al. 2019

Preprint

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The midbody is an organelle assembled at the intercellular bridge that connects the two daughter cells at the end of mitosis. It is composed of a multitude of proteins, organized in a precise and stereotyped pattern, that control the final separation of the daughter cells and prevent incorrect genome segregation. Furthermore, recent evidence indicates that the midbody is involved in many other important processes, including cell fate, pluripotency, apical-basal polarity, tissue organization, and cilium and lumen formation. Understanding the regulation and interactions of midbody proteins is therefore essential to unravel how this organelle executes its multiple functions. Here, we report the first experimentally-based characterization of the intricate midbody protein-protein interaction network (interactome), which identifies a plethora of novel interactions and provides an extremely valuable resource for dissecting the multiple roles of the midbody. Initial analysis of this interactome already revealed that PP1β/MYPT1 phosphatase regulates microtubule dynamics in late cytokinesis in part through de-phosphorylation of the kinesin component MKLP1/KIF23 of the centralspindlin complex, a key cytokinesis regulator. This de-phosphorylation antagonizes Aurora B kinase in order to modify the functions of centralspindlin and its interactions in late cytokinesis. Our findings unexpectedly expand the temporal window of activity of PP1 during mitosis and indicate that spatiotemporal changes in the distribution of kinases and counteracting phosphatases finely tune the activity of cytokinesis proteins.

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“…Given their significant role and function, primarily in cytokinesis, in contrast to other kinases (eg, Aurora B and Plk1) that have different roles throughout mitosis, 34 we believe that small molecule inhibitors targeting CIT could be promising antiproliferative compounds in the treatment of MM. Moreover, we showed that cell lines with low TP53 expression due to mutations and deletions are particularly sensitive to CIT knockdown, which suggests a potential role for CIT inhibition in relapsed/refractory patients with biallelic TP53 inactivation.…”

Section: Discussionmentioning

confidence: 99%

Citron Rho-interacting kinase silencing causes cytokinesis failure and reduces tumor growth in multiple myeloma

Şahin

Kawano

Sklavenitis-Pistofidis

et al. 2019

Blood Advances

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Key Points• CIT is upregulated in multiple myeloma.• CIT inhibition leads to cytokinesis failure and reduction in tumor burden in vitro and in vivo.Citron Rho-interacting serine/threonine kinase (CIT) is a serine/threonine kinase that acts as a key component of the midbody and is essential for cytokinesis. CIT has been reported to be highly expressed in some tumor tissues and to play a role in cancer proliferation; however, the significance of CIT has not been investigated in multiple myeloma (MM). Here, we identified, by protein microarray and immunohistochemistry, that CIT is 1 of the upregulated proteins in the plasma cells of MM patients compared with healthy controls. Analysis of a gene expression profile data set showed that MM patients with high CIT gene expression had significantly worse overall survival compared with MM patients with low CIT gene expression. CIT silencing in MM cell lines induced cytokinesis failure and resulted in decreased MM cell proliferation in vitro and in vivo. TP53 expression was found to be an independent predictor of CIT dependency, with low-TP53 cell lines exhibiting a strong dependency on CIT. This study provides the rationale for CIT being a potential therapeutic target in MM in future trials.

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Investigating cytokinesis failure as a strategy in cancer therapy

Cited by 29 publications

References 55 publications

High expression of citron kinase predicts poor prognosis of prostate cancer

High expression of citron kinase predicts poor prognosis of prostate cancer

The midbody interactome reveals new unexpected roles for PP1 phosphatases in cytokinesis

Citron Rho-interacting kinase silencing causes cytokinesis failure and reduces tumor growth in multiple myeloma

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