title: MGMT inhibition suppresses survivin expression in pancreatic cancer.
abstract: OBJECTIVE
  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.
  
  
  METHODS
  This study used standard techniques for protein and messenger RNA levels, promoter activity, protein-DNA interaction, cell viability, and correlative animal model.
  
  
  RESULTS
  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.
  
  
  CONCLUSIONS
  MGMT inhibition is associated with decrease in survivin expression and increase in sensitivity to GEM in pancreatic cancer.
authors: From the *Aurora Health Care, Milwaukee, WI; †Internal Medicine, Temple University Health Sciences Center, Philadelphia, PA; and †School of Pharmacy, Texas Tech University Health Sciences Center, Amarillo, TX.
authors: George C
authors: GC
authors: Bobustuc
authors: Anand
authors: A
authors: Patel
authors: Michael
authors: M
authors: Thompson
authors: Kalkunte S
authors: KS
authors: Srivenugopal
authors: Jacob
authors: J
authors: Frick
authors: James
authors: J
authors: Weese
authors: Santhi D
authors: SD
authors: Konduri
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology* / Q000627:therapeutic use; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use; D014408:Biomarkers, Tumor / Q000235:genetics / Q000378:metabolism*; D015153:Blotting, Western; D045744:Cell Line, Tumor; D015254:DNA Modification Methylases / Q000037:antagonists & inhibitors* / Q000235:genetics; D045643:DNA Repair Enzymes / Q000037:antagonists & inhibitors* / Q000235:genetics; D003841:Deoxycytidine / Q000031:analogs & derivatives / Q000627:therapeutic use; D015536:Down-Regulation; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects*; D006147:Guanine / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000627:therapeutic use; D006801:Humans; D051034:Inhibitor of Apoptosis Proteins / Q000235:genetics / Q000378:metabolism*; D008297:Male; D051379:Mice; D008819:Mice, Nude; D009368:Neoplasm Transplantation; D010190:Pancreatic Neoplasms / Q000188:drug therapy / Q000235:genetics* / Q000378:metabolism; D034622:RNA Interference; D011897:Random Allocation; D000077022:Survivin; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism; D025521:Tumor Suppressor Proteins / Q000037:antagonists & inhibitors* / Q000235:genetics; D000093542:Gemcitabine
chemical_list: D000970:Antineoplastic Agents; C107489:BIRC5 protein, human; D014408:Biomarkers, Tumor; D051034:Inhibitor of Apoptosis Proteins; D000077022:Survivin; D016159:Tumor Suppressor Protein p53; D025521:Tumor Suppressor Proteins; C064976:O(6)-benzylguanine; D003841:Deoxycytidine; D006147:Guanine; D015254:DNA Modification Methylases; C515491:MGMT protein, human; D045643:DNA Repair Enzymes; D000093542:Gemcitabine