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Cell cycle regulation of human pancreatic cancer by tamoxifen
E K Robinson1, A M Grau, D B Evans
1Department of Tumor Biology, The University of Texas M.D. Anderson Cancer Center, Houston 77030, USA.
Background:
Clinical trials have suggested a survival advantage for selected patients with metastatic pancreatic cancer treated with tamoxifen. We sought to identify the molecular mechanism by which tamoxifen inhibits human pancreatic cancer cell (HPCC) growth.
Methods:
HPCCs were grown in tamoxifen and growth inhibition was determined by 3H-thymidine uptake and by the MTT assay; changes in cell viability were determined by cell counts. Cell cycle alterations were evaluated by FACS, and the induction of apoptosis was evaluated using the TUNEL assay. Total cellular RNA was isolated after tamoxifen treatment, and Northern blot analysis was performed for p21waf1.
Results:
Tamoxifen inhibited HPCC growth as measured by inhibition of 3H-thymidine incorporation and by the MTT assay. However, there was no decrease in the total number of viable cells after 6 days of treatment with 10 microM of tamoxifen and no evident apoptosis, confirming the absence of a cytotoxic effect. Cell cycle analysis revealed cellular arrest in the G0/G1 phase, which correlated with p21waf1 mRNA upregulation in response to tamoxifen treatment.
Conclusions:
Tamoxifen inhibits HPCC growth by inducing G0/G1 arrest with an associated increase in p21waf1 mRNA expression. Tamoxifen is an effective inhibitor of HPCC growth in vitro and warrants further in vivo study.
Insights
Tamoxifen inhibits pancreatic cancer cell growth by halting the cell cycle in the G0/G1 phase. This mechanism involves an increase in p21waf1 mRNA expression, suggesting tamoxifen
Area of Science:
- Oncology
- Molecular Biology
- Cell Biology
Background:
- Clinical trials indicate tamoxifen may improve survival in metastatic pancreatic cancer patients.
- The precise molecular mechanisms underlying tamoxifen's effect on pancreatic cancer cell growth are not fully understood.
Purpose of the Study:
- To elucidate the molecular mechanism by which tamoxifen inhibits human pancreatic cancer cell (HPCC) growth.
- Investigate tamoxifen's impact on cell cycle progression and apoptosis in HPCCs.
Main Methods:
- HPCCs were treated with tamoxifen.
- Growth inhibition assessed via 3H-thymidine uptake and MTT assay.
- Cell cycle distribution analyzed by FACS; apoptosis evaluated using TUNEL assay.
- p21waf1 mRNA expression determined by Northern blot analysis.
Main Results:
- Tamoxifen significantly inhibited HPCC growth without reducing viable cell counts or inducing apoptosis.
- Cell cycle analysis revealed a G0/G1 phase arrest in response to tamoxifen.
- Upregulation of p21waf1 mRNA was observed following tamoxifen treatment.
Conclusions:
- Tamoxifen effectively inhibits HPCC growth by inducing G0/G1 cell cycle arrest.
- Increased p21waf1 mRNA expression is associated with tamoxifen's growth-inhibitory effect.
- Tamoxifen demonstrates potential as an in vitro inhibitor of pancreatic cancer growth, meriting further in vivo investigation.