Antisense oligonucleotides have been used to target regulatory
proteins in both in vivo and in vitro models of
prostate cancer. Our previous studies showed that
oligonucleotide-treated LNCaP
prostate cancer cells compensate for diminished expression of
B-cell chronic lymphocytic leukemia/
lymphoma 2 (BCL2), an apoptosis inhibitor, by suppressing the expression of
caspase-3 (an apoptosis promoter) while enhancing that of
serine/threonine protein kinase (AKT1) (another apoptosis inhibitor). In addition, we found an enhanced expression of the
androgen receptor (AR), its p300 and
interleukin-6 (
IL6) co-activators, polymerase transcription mediator (MED12), and growth-regulating signal transducer (STAT3). The net result was an altered pattern of gene expression often associated with more aggressive and proliferative
tumors. To further evaluate adaptive compensatory mechanisms related to
tumor resistance, aggression and proliferation, herein we evaluated the level of expression of a proliferation
antigen (KI-67) and mitosis-regulating
cyclins (B1 and D1). Compared to the relative levels of compensation detailed above, we found the expression of KI-67 to be statistically the most enhanced non-targeted
protein yet identified in compensation for suppression of BCL2. Expression of
cyclin D1 was also significantly enhanced, although to a much lesser extent. As a result, we propose that
oligonucleotide-mediated treatment could be more effective when directed towards KI-67 and BCL2. This could be accomplished by dual monospecific targeting KI-67 and BCL2, or with a bispecific (or proposed multispecific)
oligonucleotide simultaneously targeting both.