CATHEPSIN-D MATURATION AND ITS STIMULATORY EFFECT ON METASTASIS ARE PREVENTED BY ADDITION OF KDEL RETENTION SIGNAL

Cathepsin D is overexpressed in most primary breast cancers where its concentration is correlated with increased metastatic potential. To in vestigate the possible role and mechanism of this lysosomal protease i n metastasis, we transfected low-metastatic rat tumor cells with wild- type human cathepsin D, or mutated forms obtained by insertion of a KD EL peptide signal responsible for ER retention, or a control KDAS pept ide. The overexpressed pro-cathepsin D in wild-type and KDAS clones wa s normally sorted and maturated in lysosomes. In KDEL clones, pro-cath epsin D was mostly retained in the ER or partially secreted by high-pr oducer clones but was not maturated. While overexpressed cathepsin D i ncreased experimental metastasis in athymic mice, the pro-cathepsin/D- KDEL was totally ineffective. Moreover, the effect of cathepsin D on m etastasis did not seem to be due to saturation of the mannose-6-phosph ate receptor since the secretion of two other rat lysosomal enzymes wa s unaffected by cathepsin D overexpression. We conclude that pro-cathe psin D overexpression facilitates tumor metastasis only when maturated into an active enzyme.