Stimulation of colorectal cancer cell line growth by ET-1 and its inhibition by ETA antagonists

Background-The vasoactive peptide endothelin 1 (ET-1) acts via two receptor s, endothelin receptors A (ETA) and B (ETB). ET-1 is overexpressed by human cancers in vivo and in vitro and may be mitogenic for cancer cells. Method-To elucidate if ET-1 is a growth regulator the following were invest igated in human colorectal cancer cell lines (LLM1215 and HT29): ET-1 produ ction by ELISA; ET receptor expression using radioligand autoradiographic t echniques; and responsiveness to ET-1, and to ETA and ETB antagonism by gro wth measurements. Results-ET-1 was produced by LIM1215 and HT29 cells (21.3 and 41.7 fmol/ml/ 10(6) cells (24 hours); 22.6 and 71.7 fmol/ml/10(6) cells (48 hours), respe ctively). ETA and ETB receptors were expressed by both cell lines. Addition of ET-1 resulted in a dose dependent increase in cell numbers which was si gnificant at 10(-8)-10(-9) M for LIM1215, with the greatest increase at 10( -8) M (32.7% and 28.4% increase above controls at 48 hours and 72 hours; p< 0.05) and at 10(-8)-10(-9) M for HT29, with the greatest increase at 10(-9) M (13.4% and 15.7% increase above controls at 48 hours and 72 hours; p<0.0 5). ETA antagonists BQ123 and BQ610, but not the ETB antagonist BQ788, inhi bited ET-1 induced proliferation of both LIM1215 and HT29 (p<0.05). Conclusion-ET-1 can stimulate the proliferation of colorectal cancer cell l ines via the ETA, but not the ETB, receptor.