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Rubenstein M., Hollowell, C.M.P. and Guinan, P. (2013) Oligonucleotide Suppression of Bcl-2 in LNCaP Cells Is Compensated by Increased Androgen Sensitivity, p53 and Oncogene Activity, and Suppressed Caspase-3. Medical Oncology, 30, 599.

has been cited by the following article:

  • TITLE: Altered Oncogene Activity Contributes to Compensation for Antisense Suppression of Bcl-2 and Tumor Resistance

    AUTHORS: Marvin Rubenstein, Courtney M. P. Hollowell, Patrick Guinan

    KEYWORDS: Antisense Oligonucleotides, Prostate Cancer, Bcl-2, Gene Compensation, Therapy

    JOURNAL NAME: Open Journal of Apoptosis, Vol.4 No.3, July 22, 2015

    ABSTRACT: Antisense oligonucleotides (oligos) have targeted growth regulatory proteins in prostate cancer models. To identify compensatory alterations in the expression of non-targeted genes we evaluate mono- and bispecific oligos targeting and equally suppressing the expression of the apoptosis inhibitory protein bcl-2. Bcl-2 is chosen because oligos directed towards it have entered clinical trials to restore apoptosis in cancer patients. Treated LNCaP cells compensate for the diminished bcl-2 by suppressing caspase-3 (an apoptosis promoter) while enhancing expression of AKT-1 (another apoptosis inhibitor), androgen receptor (AR) and its (p300 and IL-6) coactivators. Additional proteins are enhanced including PD-1, its ligand PD-L1 (immune checkpoint blockade markers) and fas-ligand, which activate apoptosis through the signal transduction, along with suppressor protein p53, polymerase transcription mediator MED-12 and signal transducer STAT-3. These alterations in expression may contribute to a greatly enhanced expression of the proliferation marker KI-67. This suggests that therapeutic approaches to restore apoptosis through suppression of bcl-2 lead to an altered expression in non-targeted genes involving apoptosis, androgen sensitivity, transcriptional activity and immune responsiveness, leads to an increase in proliferation (and a more androgen driven aggressive phenotype). In this study we evaluate the expression of two oncogenes (v-myc and K-ras) and find a large and significant enhancement of v-myc activity, which is produced by oligos targeting bcl-2 at the 5’ position. For K-ras, although significant suppression is produced by the bispecific targeting bcl-2 at the 3’ position, the percent change is relatively small compared with other compensatory alterations we have measured, and much less than in v-myc. Therefore, for the two oncogenes being evaluated, only increased v-myc activity is probably large enough to contribute to increased tumor aggressiveness in compensation for bcl-2 suppression.