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Tamoxifen inhibits growth of oestrogen receptor-negative A549 cells
J D Croxtall1, C Emmas, J O White
1Department of Biochemical Pharmacology, William Harvey Research Institute, Medical College of St Bartholomews Hospital, London, U.K.
Abstract:
The non-steroidal anti-oestrogen tamoxifen inhibits proliferation of the A549 human lung adenocarcinoma cell line (EC50 congruent to 10 nM) yet there was no evidence of oestrogen receptor expression as determined by ligand binding assay and northern blotting. 17-beta-Oestradiol had no effect on A549 cell proliferation (1 pM-1 microM) and moreover a 100-fold excess failed to reverse the effect of 10 nM tamoxifen as did a 100-fold excess of the steroidal anti-oestrogens ICI 164384 and ICI 182780. However, 4-hydroxytamoxifen which had no significant effect on A549 cell growth (1 pM-1 microM) completely antagonized the effect of 10 nM tamoxifen when used at a 100-fold excess. In the presence of oleic acid and stearic acid (10 microM) the growth inhibitory effect of tamoxifen in A549 cells was greatly enhanced, unlike effects mediated by the anti-oestrogen binding protein described in other cells where these fatty acids had no effect. These results indicate the presence of a unique and highly sensitive mechanism in A549 cells whereby concentrations of tamoxifen relevant to classical receptor binding can inhibit cell growth in the absence of the oestrogen receptor.
Insights
Tamoxifen inhibits lung cancer cell growth without estrogen receptors, suggesting a unique cellular mechanism. This finding is crucial for understanding tamoxifen
Area of Science:
- Cell Biology
- Pharmacology
- Oncology
Background:
- Tamoxifen is a non-steroidal anti-estrogen used in cancer treatment.
- Estrogen receptors (ERs) are typically involved in tamoxifen's mechanism of action.
- A549 human lung adenocarcinoma cells are a model for studying lung cancer.
Purpose of the Study:
- To investigate the mechanism of tamoxifen's effect on A549 lung cancer cells.
- To determine if estrogen receptor expression is necessary for tamoxifen's anti-proliferative activity in these cells.
Main Methods:
- Cell proliferation assays using A549 cells.
- Ligand binding assays and northern blotting to detect estrogen receptor expression.
- Treatment with tamoxifen, 17-beta-estradiol, and other anti-estrogens (ICI 164384, ICI 182780, 4-hydroxytamoxifen).
- Assessment of fatty acid (oleic acid, stearic acid) influence on tamoxifen's effect.
Main Results:
- Tamoxifen inhibited A549 cell proliferation (EC50 ≈ 10 nM) despite the absence of detectable estrogen receptors.
- 17-beta-estradiol and other anti-estrogens did not reverse tamoxifen's effect.
- 4-hydroxytamoxifen antagonized tamoxifen's effect, suggesting a distinct interaction.
- Oleic and stearic acids significantly enhanced tamoxifen's growth inhibitory effect in A549 cells.
Conclusions:
- A549 cells possess a unique, highly sensitive mechanism for tamoxifen-induced growth inhibition.
- This mechanism operates independently of classical estrogen receptor signaling.
- Fatty acids modulate tamoxifen's efficacy in a manner not previously described for anti-estrogen binding protein pathways.