The effect of iron on prostate and breast cancer cell invasion

Whereas it has been known for sometime that malignant and nonmalignant cells require iron for their viability and proliferation, it has never been previously reported that iron may be a factor in tumor invasiveness and metastasis. In order to test this hypothesis, PC-3, a prostate cancer cell line, and MDA-MB-231, a breast cancer cell line were pre-exposed to various concentrations of iron salts, either ferric chloride or ferric ammonium citrate (FAC), and tested by assays for cell motility, invasion and adhesion. When compared to untreated cells in Matrigel(R) invasion assays, PC-3 cells treated with 100 muM. FAC or 200 muM FeCl3 had a 52 +/- 18% and 122 +/- 24% increase in invasion respectively (n=8, p<0.05). Similar results were obtained for invasion of MDA-MB-231 cells treated with 200 muM FAC and above (205 +/- 32%, n = 5, p<0.05), but not with various concentrations of FeCl3. Modified Boyden chamber cell motility assays showed 40+/-5% increase in migration after cells were treated with 100 muM FAC for PC-3 cells (n = 4) and 105 +/- 7% for MDA-MB-231 cells (n = 4). A 23 +/- 6% increase in motility occurred with 200 muM FeCl3 for MDA-MB-231 cells (n = 4). Cell adhesion to Matrigel(R) substrate was not changed by FAC or FeCl3 when adhesion was measured at either 15, 30 or 45 min. Concentrations of iron salts that were used in our studies are physiologically relevant, and at least 100-fold less than concentrations that caused loss of viability for these two cell lines. These results suggest that excess iron may have an enhancing effect on invasion and metastasis. This finding may have clinical relevance since epidemiological studies show an association between increased iron levels and iron saturation and increased risk of cancer occurrence and mortality. Postulated mechanisms by which increased dietary iron may enhance the risk of cancer development include the generation of DNA damaging oxygen free radicals and the promotion of cancer cell growth. In addition, we show that iron could possibly cause acceleration of cancer progression by enhancement of cell motility and invasion. We are now studying possible mechanisms for this effect of iron. This work was supported in part by the US Department of Defense grant PCRP/CDMRP-PC010201 and the USA Environmental Protection Agency grant R827152.