Suppression of prostate carcinoma cell invasion by expression of antisense L-plastin gene.
Based on the finding that gene expression for the actin-bundling protein L-plastin is inducible by androgen and that L-plastin is overexpressed in malignant epithelium of the prostate, we examined the functional consequences of L-plastin down-regulation in prostate carcinoma cell lines by both transfection and retroviral infection. We constructed retroviral vectors to express two different regions of the L-plastin gene, a 1713-bp 3'-coding portion and a 163-bp 5'-untranslated region, both in antisense orientation. Introduction of either constructs into prostate carcinoma cell lines, PC-3 and its isogenic but metastatic variant PC-3M cells, reduced the growth rates of both cell lines. In vitro invasion and motility of PC-3 and PC-3M cells were drastically suppressed (approximately 10-fold) by the expression of the antisense constructs. Evidence was obtained to indicate that L-plastin protein levels were indeed decreased by the antisense expression. The antisense construct for the 5'-untranslated region with the most unique sequence for the L-plastin gene was more effective in down-regulation efficiency compared with the larger antisense construct in the coding region, which maintains homology to other members of the plastin gene family. Cells infected with the 163-bp antisense virus, which were also tested in a nude mouse diaphragm invasion model, showed suppression of in vivo invasion of both PC-3 and PC-3M cells. These results suggested that overexpression of L-plastin might be functionally involved in prostate cancer invasion and metastasis, and raised the possibility that L-plastin gene-specific antisense delivery could potentially be a useful approach to interfere with prostate cancer progression in vivo.
Departments of Pathology, University of Southern California School of Medicine, Los Angeles, California, USA.
J
J
Zheng
N
N
Rudra-Ganguly
W C
WC
Powell
P
P
Roy-Burman
D000818:Animals; D016375:Antisense Elements (Genetics) / Q000235:genetics* / Q000494:pharmacology*; D002277:Carcinoma / Q000235:genetics / Q000473:pathology*; D002455:Cell Division / Q000187:drug effects; D002465:Cell Movement / Q000187:drug effects; D008297:Male; D008562:Membrane Glycoproteins; D051379:Mice; D008819:Mice, Nude; D008840:Microfilament Proteins; D009361:Neoplasm Invasiveness / Q000235:genetics / Q000473:pathology*; D010750:Phosphoproteins / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism; D011471:Prostatic Neoplasms / Q000235:genetics / Q000473:pathology*
D016375:Antisense Elements (Genetics); D008562:Membrane Glycoproteins; D008840:Microfilament Proteins; D010750:Phosphoproteins; C026742:plastin