Retinoic acid inhibits human melanoma tumor cell invasion.
The anticancer effects of retinoids have been recognized both in vivo and in vitro; however, little is known about their mechanism of action. Our study evaluated the effects of retinoic acid on the invasiveness of four human melanoma cell lines in vitro and showed a time-dependent inhibition of the ability of these cells to penetrate matrigel-coated filters. The possible mechanisms of action responsible for the anti-invasive effect were further investigated, and the data showed that retinoic acid-treated cells: (a) secreted lower levels of collagenolytic enzymes detected in type IV collagen-containing polyacrylamide gels compared with control cells, which was demonstrated by a decreased ability to degrade [3H]proline-labeled type IV collagen substrate; (b) showed a reduction in PA activity, primarily in the form of tPA, as demonstrated by chromogenic analysis; (c) showed a heterogeneous response with regard to c-myc, c-fos and c-jun mRNA expression, as determined by Northern blot analysis; and (d) demonstrated a decrease in B-actin levels and an increase in vimentin, as demonstrated by Northern blot analysis and SDS-PAGE transblot analysis. Collectively, these data suggest that RA causes an inhibitory effect on tumor cell invasion through a reconstituted basement basement membrane matrix by suppressing type IV collagenolytic activity and PA activity, which is probably triggered through a complex series of oncogene trans-acting factors, ultimately affecting cytoskeletal expression.
Wood
W R
WR
Department of Anatomy, College of Medicine, University of Arizona, Tucson 85724.
Seftor
E A
EA
Lotan
D
D
Nakajima
M
M
Misiorowski
R L
RL
Seftor
R E
RE
Lotan
R
R
Hendrix
M J
MJ
D000199:Actins / Q000378:metabolism; D002273:Carcinogens; D002455:Cell Division / Q000187:drug effects; D006801:Humans; D008545:Melanoma / Q000201:enzymology / Q000235:genetics / Q000473:pathology*; D003012:Microbial Collagenase / Q000378:metabolism; D009361:Neoplasm Invasiveness; D010960:Plasminogen Activators / Q000378:metabolism; D014212:Tretinoin / Q000494:pharmacology*; D014407:Tumor Cells, Cultured / Q000201:enzymology / Q000473:pathology; D014746:Vimentin / Q000378:metabolism
D000199:Actins; D002273:Carcinogens; D014746:Vimentin; D014212:Tretinoin; D010960:Plasminogen Activators; D003012:Microbial Collagenase