Increased prostate-specific membrane antigen expression in LNCaP cells following treatment with bispecific antisense oligonucleotides directed against bcl-2 and EGFR |
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Authors: | Marvin Rubenstein " target="_blank">Patrick Guinan |
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Institution: | (1) Division of Cellular Biology, Hektoen Institute for Medical Research, 2240 West Ogden Avenue, 2nd floor, Chicago, IL 60612, USA;(2) Division of Urology, Stroger Hospital of Cook County, Chicago, IL, USA;(3) Department of Biochemistry, Rush University Medical Center, Chicago, IL, USA;(4) Department of Urology, Rush University Medical Center, Chicago, IL, USA;(5) Department of Urology, University of Illinois, Chicago, IL 60612, USA |
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Abstract: | Antisense oligonucleotides have been employed against in vivo and in vitro prostate cancer models. While most oligos consist
of a single mRNA binding site, targeting a single gene product or others sharing sequence homology, our laboratory has developed
bispecific oligos directed toward even unrelated proteins. This study evaluates the inhibition of in vitro propagating LNCaP
cells employing mono- and bispecific oligos directed against bcl-2 the second bispecific binding site was directed against
the epidermal growth factor receptor (EGFR)]. Employing RT-PCR, the expression of non-targeted proteins encoded by mRNA for
prostate-specific membrane antigen (PSMA) and prostate-specific antigen (PSA) were subsequently evaluated. When LNCaP prostate
tumor cells were incubated with bispecific oligos (directed against bcl-2 and EGFR) and compared to lipofectin-containing
controls significant growth inhibition resulted. In subsequent experiments, the levels of mRNA encoding PSMA were unexpectedly
found to be elevated following treatment with the bispecific oligos but not with the monospecific directed solely against
bcl-2. No differences were detected in mRNA levels encoding PSA following treatment with either mono- or bispecific oligos.
Previously, we suggested that cell growth inhibition produced by some bispecifics could be attributed to complementary double-stranded
regions formed by intra-strand base pairs. Double-stranded nucleic acids are known inducers of interferon, which promote expression
of cell surface HLA type antigens. If induced, perhaps this cytokine also enhances PSMA expression, making prostate tumor
cells a more recognizable target for cytotoxic T cells. |
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