Cetrorelix, a luteinising
hormone-releasing
hormone (
LHRH) analogue, has been shown to limit growth of the human
androgen-independent prostate cell line DU-145, although other inhibitory actions may also be affected. Both growth and invasion of DU-145 cells are linked to autocrine
epidermal growth factor receptor (EGFR) signalling. Invasiveness requires not only cells to migrate to conduits, but also reduced adhesiveness between tumour cells to enable separation from the tumour mass. Thus, we investigated whether
Cetrorelix alters the DU-145 cell-cell adhesion and if this occurs via altered EGFR signalling. Pharmacologic levels of
Cetrorelix limited the invasiveness of a highly invasive DU-145 subline overexpressing full-length EGFR (DU-145 WT). Extended exposure of the cells to
Cetrorelix resulted in increased levels of the cell-cell adhesion complex molecules
E-cadherin, alpha- and
beta-catenin, and p120.
Puromycin blocked the increases in
E-cadherin and
beta-catenin levels, suggesting that de novo
protein synthesis is required. The
Cetrorelix effect appears to occur via transmodulation of EGFR by a
protein kinase C (PKC)-dependent mechanism, as there were no changes in DU-145 cells expressing EGFR engineered to negate the PKC transattenuation site (DU-145 A654); downregulation of EGFR signalling produced a similar upregulation in adhesion complex
proteins, further suggesting a role for autocrine signalling.
Cetrorelix increased the cell-cell adhesiveness of DU-145 WT cells to an extent similar to that seen when autocrine EGFR signalling is blocked; as expected, DU-145 A654 cell-cell adhesion also was unaffected by
Cetrorelix. The increased adhesiveness is expected as the adhesion complex molecules moved to the cells' periphery. These data offer direct insight into the possible crosstalk pathways between the
LHRH and EGFR receptor signalling. The ability of
Cetrorelix to downregulate EGFR signalling and subsequently reverse the antiadhesiveness found in metastatic
prostate cancer highlights a novel potential target for therapeutic strategies.