The functional role of ADAMTS-1 and -15 in prostate cancer progression

Introduction:
Prostate cancer is a leading cause of cancer death in men. Death is usually
a consequence of castration resistant tumour progression. Some metalloproteinases are
implicated in the process of cancer progression. ADAMTS proteinases (A Disintegrin
And Metalloproteinase with ThromboSpondin motifs) are metalloproteinases that play
diverse roles in tissues. Prostate cancer cells express ADAMTS-1 and -15 but the role
played by these proteinases in prostate cancer progression is unknown. This study was
designed to determine the role of ADAMTS-1 and 15 in prostate cancer progression.

Materials & Methods:
Prostate cancer and stromal cell tumour spheroids were grown in
3-dimensional culture in ECM gel containing a quenched-fluorescent substrate. The
tumour spheroids were observed for evidence of proteolytic activity. Prostate cancer
cells were treated with DHT and TNF. Changes in expression of ADAMTS-1 and -15
were analysed. ADAMTS-1 and -15 expression was knocked-down in PC3 prostate
cancer cells and the effect of knock-down on proliferation, migration and invasion was
analysed.

Results:
Tumour spheroids emitted fluorescence after approximately 24 hours in
culture, indicating proteolytic activity. DHT and TNF down-regulated ADAMTS-15
expression in LNCaP cells and stromal cells respectively. The validated anti-ADAMTS-
15 antibody detected 50kDa bands, suggesting a novel cleavage site within the
disintegrin-like domain of ADAMTS-15. ADAMTS-1 and 15 knock-down had no
effect on proliferation, migration or invasion of PC3 prostate cancer cells.

Conclusions:
Prostate cancer and stromal cells degrade components of the surrounding
ECM. ADAMTS-15 but not ADAMTS-1 expression is androgen and TNF-regulated.
ADAMTS-1 and 15 expression do not affect the proliferation, migration or invasive
potential of PC3 cells in vitro. Cleavage of ADAMTS-15 in the disintegrin-like domain
results in the release of a C-terminal fragment with potential anti-angiogenic properties.
Down-regulation by DHT in prostate cancer cells suggests that ADAMTS-15 could be
playing an anti-tumour role in prostate cancer progression.