PO-147 Pinostilbene hydrate suppresses human oral cancer cell metastasis via downregulation matrix metalloproteinase-2 through the mitogen-activated protein kinase signalling pathway

Abstract

IntroductionAcute myeloid leukaemia (AML) is the most common acute leukaemia in adults and has one of the poorest survival rates of all cancers. Despite advancements in treatments, the 5 year survival rate for AML remains at 26%, and is less than 8% for patients aged over 60. Approximately one-third of patients exhibit primary refractory disease, however, the mechanisms controlling this have not been fully elucidated. Overexpression of the brain and acute leukaemia, cytoplasmic (BAALC) gene is a negative prognostic factor for AML and is associated with primary refractory disease, but precisely how overexpression of BAALC is controlling sensitivity to chemotherapeutics is unknown. As AML cells with perturbations in DNA repair pathways exhibit alterations in sensitivity/resistance to a range of chemotherapeutics, we examined whether BAALC overexpression perturbs DNA repair pathways in AML cells.Material and methodsBAALC was overexpressed in a panel of AML cells and their ability to repair DNA damage was measured by western blot and comet assay. Alterations in expression of key DNA damage repair genes were measured by PCR in BAALC overexpressing and empty vector (EV) control cells. BAALC-mediated signalling complexes involved in DNA repair were identified by immunoprecipitation.Results and discussionsBAALC, but not EV, overexpression resulted in elevated DNA fragmentation (comet assay), and sustained gH2AX and ATM activation (pSer1981) post-daunorubicin and etoposide-induced DNA damage, indicative of an inability to repair the damage. Gene expression analyses in BAALC overexpressing cells identified that the expression of components (RAD51D, TP53BP1, BTG2) of the high-fidelity homologous recombination double strand break repair pathway were significantly decreased. Furthermore, BAALC interacts with several proteins (RAD51, CaMKII, dermcidin) implicated in DNA repair. Further supporting a role for BAALC overexpression in inducing defective homologous recombination repair, BAALC overexpressing AML cells were hypersensitive to cisplatin treatment.ConclusionAs perturbations in DNA repair pathways in AML have been associated with increased resistance to a range of chemotherapeutics, and BAALC overexpression is associated with primary refractory AML, our data suggests that BAALC overexpression induces decreased chemosensitivity by perturbing DNA repair pathways.