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.
Highlights
High-grade brain tumors (HGBT) represent an important unmet medical challenge
Western blot analysis revealed that Citron kinase protein (CITK) levels were still suppressed by both siRNAs after 200 h for D283 and 144 h for D341 (Figure S1A)
Since cytokinesis failure is the most knowneffect of CITK loss in both sensitive normal tissues and tumor cells [28,33], we investigated whether this phenotype occurs in Group 3 and Group 4 (G3/G4) MB cell lines
Summary
High-grade brain tumors (HGBT) represent an important unmet medical challenge. In pediatric age, the most common HGBT is medulloblastoma (MB), which has been classified into four biological subgroups, based on microarray and genomic sequencing technologies (WNT, SHH, Group 3 andGroup 4) [1,2,3]. High-grade brain tumors (HGBT) represent an important unmet medical challenge. The most common HGBT is medulloblastoma (MB), which has been classified into four biological subgroups, based on microarray and genomic sequencing technologies Group 4) [1,2,3]. WNT and SHH MB subgroups are primarily driven by mutations leading to constitutive activation of the Wingless and Sonic Hedgehog signaling pathways, respectively. MBs are clearly separable across the majority of transcriptional and methylation profiling studies, demonstrating minimal overlap with other subgroups [1]. Group 4 medulloblastoma are more similar to each other since several cytogenetic features, such as Cancers 2020, 12, 542; doi:10.3390/cancers12030542 www.mdpi.com/journal/cancers.
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