Abstract
We have previously demonstrated that Myc-overexpressing medulloblastoma cells are sensitive to apoptosis induction in response to mitotic inhibition with an Aurora kinase B inhibitor. Profiling of differential mRNA expression by microarray and RT-PCR revealed that alpha cardiac actin 1 (ACTC1) mRNA expression is upregulated in cells resistant to apoptosis triggered by Aurora kinase B inhibition and this upregulation is absent in Myc-overexpressing cells. We confirmed expression of ACTC1 protein by Western blot in SHH subgroup (DAOY, UW228, UW426) and Group 3 subgroup cell lines (D458, D425) and observed that expression is lower in Group 3 cells. These findings were further validated by analysis of ACTC1 mRNA expression among all four medulloblastoma subgroups by microarray in a set of 763 medulloblastomas which revealed increased expression of ACTC1 in SHH and WNT subgroups compared to Group 3 and Group 4. Inhibition of Aurora kinase B in SHH cells that overexpress Myc results in a reduction in ACTC1 protein level after 96 hours and this is not observed in the isotype control cells with basal Myc expression. Reduction in ACTC1 protein levels in SHH cells overexpressing Myc is associated with Caspase 3 cleavage. ACTC1 may play a role in blocking apoptosis triggered by mitotic inhibition in medulloblastoma. Further experiments to test this hypothesis are planned. These finding could potentially impact on chemotherapy choice in the treatment of SHH and WNT tumours, which demonstrate increased ACTC1 expression.