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

Abstract

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 .

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

“…3 Another study suggested that citron kinase protein might be a potential target for medulloblastoma treatment. 19 Cytokinesis failure can cause polyploidy, which is an irreversible process that prevents cell division and may lead to a reduction in tumor burden. 20 In contrast, polyploidy can lead to chromosomal instability and increase tumorigenicity.…”

The Yin and Yang of Autosomal Recessive Primary Microcephaly Genes: Insights from Neurogenesis and Carcinogenesis

“…MCPH4, MCPH7, MCPH8, MCPH10, MCPH13, MCPH17, MCPH19, and MCPH23 are highly expressed in different tumor tissues or cancer cell lines, indicating that some MCPH genes can be considered as oncogenes or potential cancer biomarkers [24][25][26][27][28][29][30][31]. The knockdown or inhibited expression of these genes may be a potential therapeutic method for cancer treatment [31][32][33]. In addition, the overexpression of MCPH2, MCPH5, MCPH7, MCPH14, MCPH20, MCPH21, MCPH23, and MCPH24 is associated with aggressiveness and poor outcome in patients with cancer [28,[34][35][36][37][38][39].…”

“…Apoptosis of neuronal progenitors [76,77] Cell cycle and apoptosis (colon cancer, CC) [26] DNA damage, proliferation, cell senescence and apoptosis (medulloblastoma) [33] MCPH18 (WDFY3)…”

“…Inducible knockdown of MCPH7 in cancer cells in vitro decreased CDK1/CYCLIN B activity and induced apoptosis [115]. In medulloblastoma cell lines and mouse models, the absence or deletion of MCPH17 increased apoptosis, thus suggesting its potential role in medulloblastoma treatment [33]. In addition, the apoptosis rate was increased in MCPH19 knockdown PCa cells [82].…”

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

“…In addition, CITK loss leads to accumulation of DNA double strand breaks (DSB), strongly activating the P53 signaling pathway in developing central nervous system [16]. We have shown that CITK loss induces apoptosis and cell senescence in SHH MB cells and reduces growth of both xenograft and transgenic MB [31]. Interestingly, these anti-proliferative effects of CITK loss may be engaged through TP53-dependent and TP53-independent mechanisms [16,31].…”