title: Oligonucleotide suppression of bcl-2 in LNCaP cells is compensated by increased androgen sensitivity, p53 and oncogene activity, and suppressed caspase-3.
abstract: Antisense oligonucleotides (oligos) have been employed against prostate cancer models in both in vivo and in vitro systems. While most target growth factors or their receptors, other oligos are directed against inhibitors of apoptosis or mediators of androgen action. Those which suppress bcl-2 activity (in prostate cancer patients) have even reached clinical trials. We evaluated a set of oligos which targeted and comparably suppressed the expression of bcl-2, an apoptosis inhibitory protein. Our first study reported that LNCaP cells were adapted by suppression of caspase-3 (a promoter of apoptosis). In this study we evaluated additional proteins associated with tumor progression and found the expression of the androgen receptor, its p300 and IL-6 co-activators, as well as v-myc (oncogenic) and (unexpectedly) tumor suppressor p53 genes to be enhanced. We conclude that oligo treatment directed against bcl-2, intended to stimulate apoptosis, can be evaded through compensatory changes in gene activity associated with additional regulators of apoptosis, androgen sensitivity and oncogenesis. This suggests that therapeutic suppression of bcl-2 can promote tumor resistance and transformation to a more aggressive (androgen and oncogene driven) phenotype.
authors.affiliation: Division of Cellular Biology, Hektoen Institute for Medical Research, 2240 West Ogden Avenue, 2'nd floor, Chicago, IL 60612, USA. DrMarv@Prodigy.net
authors.forename: Marvin
authors.initials: M
authors.lastname: Rubenstein
authors.forename: Courtney M P
authors.initials: CM
authors.lastname: Hollowell
authors.forename: Patrick
authors.initials: P
authors.lastname: Guinan
mesh_terms: D000728:Androgens / Q000235:genetics*; D053148:Caspase 3 / Q000235:genetics*; D045744:Cell Line, Tumor; D050881:E1A-Associated p300 Protein / Q000235:genetics; D006801:Humans; D015850:Interleukin-6 / Q000235:genetics; D020780:Matrix Metalloproteinase 9 / Q000235:genetics; D009841:Oligonucleotides / Q000235:genetics*; D016376:Oligonucleotides, Antisense / Q000235:genetics; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000235:genetics; D016271:Proto-Oncogene Proteins c-myc / Q000235:genetics; D011944:Receptors, Androgen / Q000235:genetics; D016159:Tumor Suppressor Protein p53 / Q000235:genetics*; D051153:Wnt Proteins / Q000235:genetics
chemical_list: C410798:AR protein, human; D000728:Androgens; D015850:Interleukin-6; D009841:Oligonucleotides; D016376:Oligonucleotides, Antisense; D019253:Proto-Oncogene Proteins c-bcl-2; D016271:Proto-Oncogene Proteins c-myc; D011944:Receptors, Androgen; D016159:Tumor Suppressor Protein p53; D051153:Wnt Proteins; C540523:Wnt11 protein, human; D050881:E1A-Associated p300 Protein; C494360:EP300 protein, human; D053148:Caspase 3; D020780:Matrix Metalloproteinase 9