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

Abstract

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.

High Expression of Citron Kinase Contributes to the Development of Esophageal Squamous Cell Carcinoma

“…Previous studies have found that p27 acts as a tumor suppressor by closely binding to CIT to prevent its interaction with its activator RhoA, thereby regulating cytokinesis ( Serres et al, 2012 ). Recently, a study has found that inactivation of CIT significantly reduces RAD51, a factor that helps to repair DNA damage, thus causing accumulation of DNA damage in medulloblastoma cells and finally leading to apoptosis ( Pallavicini et al, 2020 ). In the current study, the microarray results revealed several key regulators that may be controlled by CIT.…”

Inhibiting microcephaly genes as alternative to microtubule targeting agents to treat brain tumors

“…It has been demonstrated that CITK could be a potential target for medulloblastoma treatment [ 128 , 129 ]. CITK knockdown by RNAi in SHH, Group 3 and 4 medulloblastoma cell lines impairs proliferation, induces cytokinesis failure, cell cycle arrest, and apoptosis via TP53-dependent and TP53 independent mechanisms [ 128 – 130 ].…”

“…Moreover, all CITK-depleted cell lines show an accumulation of DNA damage, consistent with data obtained in neural progenitors of null mice [ 49 ]. Interestingly, these cells show also reduced level of the DNA-repair protein RAD51 and impairment of homologous recombination [ 129 ]. Lastly, CITK knockdown in MB cells potentiates the effect of radiation and cisplatin treatment [ 129 ].…”

Oncogenic FGFR Fusions Produce Centrosome and Cilia Defects by Ectopic Signaling

“…CIT functions in spindle orientation and during late cytokinesis [300][301][302][303]. CIT overexpression has been associated with cancers of various origin [304][305][306][307][308][309][310], likely through its kinase function that is, however, lost during chromosomal rearrangement in the FGFR2-CIT fusion (Figure 1). Transgenic mice expressing CIT variant lacking the kinase domain show defects in neurogenesis and spermatogenesis [311,312], due to aberrant cytokinesis that is followed by massive apoptosis.…”