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Updated: Apr 14, 2026
Studying Pancreatic Cancer Stem Cell Characteristics for Developing New Treatment Strategies
Published on: June 20, 2015
MGMT inhibition suppresses survivin expression in pancreatic cancer
George C Bobustuc1, Anand Patel, Michael Thompson
1From 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.
Objectives:
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.
Insights
Inhibiting O-methylguanine DNA methyltransferase (MGMT) reduces survivin expression in pancreatic cancer. This suggests MGMT inhibition enhances sensitivity to gemcitabine (GEM) chemotherapy.
Area of Science:
- Oncology
- Molecular Biology
- Cancer Research
Background:
- Survivin, an antiapoptotic gene, is overexpressed in cancers and linked to chemotherapy resistance.
- The tumor suppressor p53 normally inhibits survivin.
- The interplay between MGMT and survivin in cancer is not fully understood.
Purpose of the Study:
- To investigate the regulatory relationship between MGMT and survivin.
- To determine if MGMT inhibition affects survivin expression and chemosensitivity.
Main Methods:
- Assessed protein and mRNA levels, promoter activity, and protein-DNA interactions.
- Utilized cell viability assays and an animal model.
- Employed O-benzylguanine (BG) to inhibit MGMT and small interfering RNA for gene silencing.
Main Results:
- O-benzylguanine (BG) inhibited survivin expression in pancreatic cancer cells.
- Silencing MGMT reduced survivin transcription, while p53 inhibition increased both MGMT and survivin.
- BG treatment decreased survivin and PCNA levels in tumors, correlating with enhanced gemcitabine sensitivity.
Conclusions:
- MGMT inhibition leads to decreased survivin expression in pancreatic cancer.
- Targeting MGMT enhances sensitivity to gemcitabine chemotherapy.
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