A New Way to Treat Brain Tumors: Targeting Proteins Coded by Microcephaly Genes?

Lang, Patrick; Gershon, Timothy R.

doi:10.1002/bies.201700243

Cited by 18 publications

(11 citation statements)

References 154 publications

(187 reference statements)

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“…The development of such molecules will therefore represent a crucial topic for future research. As a final remark, our work adds further support to the emerging view that many genes implicated in genetic microcephaly may represent promising targets for brain tumors treatment (67).…”

Section: Discussionsupporting

confidence: 65%

Inactivation of Citron Kinase Inhibits Medulloblastoma Progression by Inducing Apoptosis and Cell Senescence

et al. 2018

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Medulloblastoma is the most common malignant brain tumor in children. Current treatment for medulloblastoma consists of surgery followed by irradiation of the whole neuraxis and high-dose multiagent chemotherapy, a partially effective strategy associated with highly invalidating side effects. Therefore, identification and validation of novel target molecules capable of contrasting medulloblastoma growth without disturbing brain development is needed. Citron kinase protein (CITK), encoded by primary microcephaly gene , is required for normal proliferation and survival of neural progenitors. Constitutive loss of CITK leads to cytokinesis failure, chromosome instability, and apoptosis in the developing brain, but has limited effects on other tissues. On this basis, we hypothesized that CITK could be an effective target for medulloblastoma treatment. In medulloblastoma cell lines DAOY and ONS-76, CITK knockdown increased both cytokinesis failure and DNA damage, impairing proliferation and inducing cell senescence and apoptosis via TP53 or TP73. Similar effects were obtained in the NeuroD-SmoA1 transgenic mouse model, in which CITK deletion increased apoptotic cells and senescence markers such as P21, P27, and P16 Most importantly, CITK deletion decreased tumor growth and increased overall survival in these mice, with no apparent side effects. These results suggest that CITK can be a useful molecular target for medulloblastoma treatment. and proof of concept identifies citron kinase protein as a suitable target for medulloblastoma treatment. http://cancerres.aacrjournals.org/content/canres/78/16/4599/F1.large.jpg .

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Section: Discussionsupporting

confidence: 65%

Inactivation of Citron Kinase Inhibits Medulloblastoma Progression by Inducing Apoptosis and Cell Senescence

et al. 2018

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“…Strict control of progenitor proliferation and differentiation are required for brain growth. Inadequate proliferation causes microcephaly whereas excessive proliferation may support tumorigenesis (Chizhikov and Millen, 2003;Grimmer and Weiss, 2006;Yang et al, 2009;Garel et al, 2011;Lang and Gershon, 2018). Cerebellar growth depends on the proliferation of cerebellar granule neuron progenitors (CGNPs), which continues into postnatal life (Ten Donkelaar and Lammens, 2009;Marzban et al, 2015).…”

Section: Introductionmentioning

confidence: 99%

GSK-3 modulates SHH-driven proliferation in postnatal cerebellar neurogenesis and medulloblastoma

et al. 2019

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Cerebellar development requires regulated proliferation of cerebellar granule neuron progenitors (CGNPs). Inadequate CGNP proliferation causes cerebellar hypoplasia whereas excessive CGNP proliferation can cause medulloblastoma, the most common malignant pediatric brain tumor. Although sonic hedgehog (SHH) signaling is known to activate CGNP proliferation, the mechanisms downregulating proliferation are less defined. We investigated CGNP regulation by GSK-3, which downregulates proliferation in the forebrain, gut and breast by suppressing mitogenic WNT signaling in mouse. In striking contrast to these systems, we found that co-deleting Gsk3a and Gsk3b blocked CGNP proliferation, causing severe cerebellar hypoplasia. The GSK-3 inhibitor CHIR-98014 similarly downregulated SHH-driven proliferation. Transcriptomic analysis showed activated WNT signaling and upregulated Cdkn1a in Gsk3a/b-deleted CGNPs. Ctnnb co-deletion increased CGNP proliferation and rescued cerebellar hypoproliferation in Gsk3a/b mutants, demonstrating physiological control of CGNPs by GSK-3, mediated through WNT. SHH-driven medulloblastomas similarly required GSK-3, as co-deleting Gsk3a/b blocked tumor growth in medulloblastoma-prone SmoM2 mice. These data show that a GSK-3/WNT axis modulates the developmental proliferation of CGNPs and the pathological growth of SHH-driven medulloblastoma. The requirement for GSK-3 in SHH-driven proliferation suggests that GSK-3 may be targeted for SHH-driven medulloblastoma therapy.

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“…Although the cellular origin of the different MB subtypes is still debated, it is clear that MB cells share many molecular features with cerebellar granule progenitors and radial glia cells [8,9]. Genes mutated in primary microcephaly syndromes (MCPH) are attractive targets for brain-tumor-directed drug development [10,11]. MCPH is a rare and genetically heterogeneous disorder, in which brain volume is strongly reduced, as compared to the rest of the body [12].…”

Section: Introductionmentioning

confidence: 99%

CITK Loss Inhibits Growth of Group 3 and Group 4 Medulloblastoma Cells and Sensitizes Them to DNA-Damaging Agents

Pallavicini

Iegiani

Berto

et al. 2020

Cancers

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Medulloblastoma (MB) is the most common malignant brain tumor in children, and it is classified into four biological subgroups: WNT, Sonic Hedgehog (SHH), Group 3 and Group 4. The current treatment is surgery, followed by irradiation and chemotherapy. Unfortunately, these therapies are only partially effective. Citron kinase protein (CITK) has been proposed as a promising target for SHH MB, whose inactivation leads to DNA damage and apoptosis. D283 and D341 cell lines (Group 3/Group 4 MB) were silenced with established siRNA sequences against CITK, to assess the direct effects of its loss. Next, D283, D341, ONS-76 and DAOY cells were treated with ionizing radiation (IR) or cisplatin in combination with CITK knockdown. CITK depletion impaired proliferation and induced cytokinesis failure and apoptosis of G3/G4 MB cell lines. Furthermore, CITK knockdown produced an accumulation of DNA damage, with reduced RAD51 nuclear levels. Association of IR or cisplatin with CITK depletion strongly impaired the growth potential of all tested MB cells. These results indicate that CITK inactivation could prevent the expansion of G3/G4 MB and increase their sensitivity to DNA-damaging agents, by impairing homologous recombination. We suggest that CITK inhibition could be broadly associated with IR and adjuvant therapy in MB treatment.

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A New Way to Treat Brain Tumors: Targeting Proteins Coded by Microcephaly Genes?

Cited by 18 publications

References 154 publications

Inactivation of Citron Kinase Inhibits Medulloblastoma Progression by Inducing Apoptosis and Cell Senescence

Inactivation of Citron Kinase Inhibits Medulloblastoma Progression by Inducing Apoptosis and Cell Senescence

GSK-3 modulates SHH-driven proliferation in postnatal cerebellar neurogenesis and medulloblastoma

CITK Loss Inhibits Growth of Group 3 and Group 4 Medulloblastoma Cells and Sensitizes Them to DNA-Damaging Agents

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