Author(s)

Marvin Rubenstein^1,2,3,4*, Courtney M. P. Hollowell², Patrick Guinan^1,2,4,5

¹Division of Cellular Biology, Hektoen Institute for Medical Research, Chicago, IL, USA.
²Division of Urology, Stroger Hospital of Cook County, Chicago, IL, USA.
³Department of Biochemistry, Rush University Medical Center, Chicago, IL, USA.
⁴Department of Urology, Rush University Medical Center, Chicago, IL, USA.
⁵Department of Urology, University of Illinois at Chicago, Chicago, IL, IL, USA.

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.

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

Rubenstein, M. , Hollowell, C. and Guinan, P. (2015) Altered Oncogene Activity Contributes to Compensation for Antisense Suppression of Bcl-2 and Tumor Resistance. Open Journal of Apoptosis, 4, 62-70. doi: 10.4236/ojapo.2015.43007.