Matriptase and its cognate inhibitor,
hepatocyte growth factor activator inhibitor-1 (HAI-1), have been implicated in
carcinoma onset and malignant progression. However, the pathological mechanisms of
matriptase activation are not defined.
Steroid sex hormones play crucial roles in prostate and
breast cancer. Therefore, we investigated the questions of whether and how
steroid sex hormones regulate
matriptase activation in these
cancer cells. Treatment of cells with 17beta-estradiol had no effect on activation of
matriptase in
hormone-starved
breast cancer cells, in part due to their high constitutive level of activated
matriptase. In striking contrast, very low levels of activated
matriptase were detected in
hormone-starved lymph node prostatic
adenocarcinoma (LNCaP) cells. Robust activation of
matriptase was observed as early
as 6 h after exposure of these cells to 5alpha-dihydrotestosterone (DHT). Activation of
matriptase was closely followed by shedding of the activated
matriptase with >90% of total activated
matriptase present in the
culture media 24 h after DHT treatment. Activated
matriptase was shed in a complex with HAI-1 and may result from simultaneously proteolytic cleavages of both membrane-bound
proteins. Latent
matriptase and free HAI-1 were also shed into
culture media. As a result of shedding, the cellular levels of
matriptase and HAI-1 were significantly reduced 24 h after exposure to DHT. DHT-induced
matriptase activation and shedding were significantly inhibited by the
androgen antagonist bicalutamide, by the
RNA transcription inhibitor
actinomycin D, and by the
protein synthesis inhibitor cycloheximide. These results suggest that in LNCaP cells,
androgen induces
matriptase activation via the
androgen receptor, and requires transcription and
protein synthesis.