MGMT inhibition suppresses survivin expression in pancreatic cancer

Survivin, an antiapoptotic gene inhibited by p53, is overexpressed in human cancers and correlates with chemotherapy resistance. Here, we investigated the mutual regulatory mechanism between MGMT (O-methylguanine DNA methyltransferase) and survivin. This study used standard techniques for protein and messenger RNA levels, promoter activity, protein-DNA interaction, cell viability, and correlative animal model. O-benzylguanine (BG), a potent inhibitor of MGMT (a DNA repair protein), curtails the expression of survivin in pancreatic cancer. Silencing MGMT by small interfering RNA down-regulates survivin transcription. p53 inhibition enhances MGMT and survivin expressions. When p53 was silenced, BG-induced MGMT inhibition was not associated with the down-regulation of survivin, underscoring the regulatory role of p53 in the MGMT-survivin axis. O-benzylguanine inhibits survivin and PCNA (proliferating cell nuclear antigen) at messenger RNA and protein levels in PANC-1 and L3.6pl cells and decreases survivin promoter activity via increased p53 recruitment to the survivin promoter. In orthotopic pancreatic xenografts established in nude mice, BG ± gemcitabine (GEM) decrease survivin expression in tumor tissue; protein levels and immunohistochemistry show significant decrease in survivin and PCNA levels, which correlate with increased sensitivity to GEM. MGMT inhibition is associated with decrease in survivin expression and increase in sensitivity to GEM in pancreatic cancer.