Tissue inhibitors of
metalloproteinases (TIMPs) have been shown to perform several biological functions in
tumor promotion, principally by their action of inhibiting
matrix metalloproteinases (
MMPs) at different steps of the metastatic process. In particular,
TIMP-2 is involved in a functional complex with the membrane-type 1 (MT1)
MMP to convert the secreted MMP-2
progelatinase into the fully active
proteolytic enzyme. We used the human,
androgen-sensitive prostate
carcinoma cell line LNCaP in coculture with the human
osteosarcoma cell line OHS to experimentally address the possibility of
androgen-dependent regulatory effects on the functional MT1-
MMP/TIMP-2/
MMP-2 complex upon interaction between prostate
carcinoma and osteoblastic cells in
metastasis of
prostate cancer to bone. In the LNCaP cells a gradual, time-dependent decline in
TIMP-2 mRNA expression was observed in the presence of the
synthetic androgen analogue
R1881 (100 nM), reaching approximately 25% of the control level after 48 h of incubation. Consistent with this, the accumulation of secreted
TIMP-2 in media from R1881-treated cells was significantly inhibited already after 3 h. Neither MMP-2 gelatinolytic activity nor expression of
MT1-MMP was detected in LNCaP cells. In contrast, the OHS cells showed membrane-associated
MT1-MMP expression as well as MMP-2 secretion. However,
R1881 treatment of the LNCaP/OHS coculture model did not seem to change the overall proteolytic activity of the MT1 -
MMP/TIMP-2/
MMP-2 complex. Hormonal control of
TIMP-2 expression in prostate
carcinoma cells has not been previously reported, but whether such regulation has any functional role in the development of osteoblastic
metastases in
prostate cancer is still unclear.