Abstract A251: MGMT inhibition decreases survivin expression in pancreatic cancer.

Abstract

Abstract Survivin is an antiapoptotic gene negatively regulated by p53 tumor suppressor. Survivin is overexpressed in human cancers and one of its functions is to reduce the efficacy of chemotherapy. We report that O6-benzylguanine (BG), a potent inhibitor of MGMT (O6-methyl guanine DNA methyl transferase), a DNA repair protein, curtails the expression of survivin in pancreatic cancer cells. We also show that BG, either alone or in combination with gemcitabine, inhibits survivin and PCNA expression both at the mRNA and protein levels in Panc1 and L3.6pl cells. Further, BG, either alone or in combination with gemcitabine, significantly decreases survivin promoter activity in these cells. We also show that these combinations decrease survivin protein expression in pancreatic tumors derived from orthotopic xenografts developed in nude mice. Immunohistochemistry confirms the reduced expression of survivin and PCNA in tumor sections after BG or BG plus gemcitabine treatments. We also show the enhanced recruitment of p53 protein to the survivin promoter in BG-treated pancreatic cancer cells. Further, BG promotes p53 function leading to growth inhibition. Taken together our data suggests that BG induced partial restoration of p53 activity suppresses survivin function and enhances gemcitabine effect in pancreatic cancer. Citation Information: Mol Cancer Ther 2013;12(11 Suppl):A251. Citation Format: George C. Bobustuc, Anand Patel, Michael Thompson, Srivenugopal S. Kalkunte, Jacob Frick, James Weese, Santhi D. Konduri. MGMT inhibition decreases survivin expression in pancreatic cancer. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2013 Oct 19-23; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2013;12(11 Suppl):Abstract nr A251.