title: Suppression of BCL2 by Antisense Oligonucleotides and Compensation by Non-Targeted Genes May Enhance Tumor Proliferation.
abstract: 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.
authors.affiliation: Division of Cellular Biology, Hektoen Institute for Medical Research, Chicago, IL, U.S.A. Division of Urology, Stroger Hospital of Cook County, Chicago, IL, U.S.A. Department of Biochemistry, Rush University Medical Center, Chicago, IL, U.S.A. Department of Urology, Rush University Medical Center, Chicago, IL, U.S.A. DrMarv@Prodigy.net.
authors.forename: Marvin
authors.initials: M
authors.lastname: Rubenstein
authors.affiliation: Division of Urology, Stroger Hospital of Cook County, Chicago, IL, U.S.A.
authors.forename: Courtney M P
authors.initials: CM
authors.lastname: Hollowell
authors.affiliation: Division of Cellular Biology, Hektoen Institute for Medical Research, Chicago, IL, U.S.A. Division of Urology, Stroger Hospital of Cook County, Chicago, IL, U.S.A. Department of Urology, Rush University Medical Center, Chicago, IL, U.S.A. Department of Urology, University of Illinois at Chicago, Chicago, IL, U.S.A.
authors.forename: Patrick
authors.initials: P
authors.lastname: Guinan
mesh_terms: D051017:Apoptosis Regulatory Proteins / Q000096:biosynthesis; D053148:Caspase 3 / Q000096:biosynthesis; D045744:Cell Line, Tumor; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D015850:Interleukin-6 / Q000096:biosynthesis; D019394:Ki-67 Antigen / Q000096:biosynthesis* / Q000235:genetics; D008297:Male; D009363:Neoplasm Proteins / Q000096:biosynthesis / Q000235:genetics; D016376:Oligonucleotides, Antisense / Q000627:therapeutic use*; D011471:Prostatic Neoplasms / Q000235:genetics* / Q000473:pathology / Q000628:therapy*; D051057:Proto-Oncogene Proteins c-akt / Q000096:biosynthesis / Q000235:genetics; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000037:antagonists & inhibitors / Q000235:genetics*
chemical_list: D051017:Apoptosis Regulatory Proteins; C508600:IL6 protein, human; D015850:Interleukin-6; D019394:Ki-67 Antigen; D009363:Neoplasm Proteins; D016376:Oligonucleotides, Antisense; D019253:Proto-Oncogene Proteins c-bcl-2; C494918:AKT1 protein, human; D051057:Proto-Oncogene Proteins c-akt; D053148:Caspase 3
keywords: Antisense; BCL2; KI-67; compensation; gene therapy; prostate cancer