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Following Inhibition of BCL-2 by Antisense Oligonucleotides Compensatory Suppression of Apoptosis Involves the Direct Signal Transduction Pathway of LNCaP Cells

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ABSTRACT
Previously we have shown that when LNCaP cells are treated with antisense oligonucleotides (oligos) directed against BCL-2, compensatory changes in non-targeted genes take place in attempts to restore apoptosis and promote tumor aggressiveness. In addition to the inhibition of BCL-2, we find that the apoptosis promoter caspase-3 activity is suppressed, the transcription activity of STAT-3 is enhanced, while other regulators (bax, clusterin, AKT-1) associated with mitochondrial regulated apoptosis and caspase cascade are either unchanged or undetectable. We now evaluate proteins associated with the second pathway of apoptosis activation mediated by direct signal transduction involving fas, fas-ligand (a tumor necrosis factor-like cell surface receptor aka CD95), as well as the similar programmed death cell surface receptor (PD-1) and its respective ligand (PD-1L). This study evaluates the growth inhibition of in vitro propagating LNCaP cells employing mono- and bispecific oligos directed against BCL-2 [the second binding site was directed against the epidermal growth factor receptor (EGFR)]; and employing RT-PCR. The expression of these four proteins was evaluated. Expression of fas-ligand, PD-1 and PD-L1 were all significantly enhanced, whereas fas itself was undetectable. This suggests that in addition to pathways associated with the mitochondrial pathway of apoptosis, compensatory changes occur in the direct signal transduction pathway of this process. In addition to alterations in androgen sensitivity, growth factor expression and oncogene expression, these data suggest that suppressive BCL-2 therapy involves multiple pathways, including those involved with immune targeting and cytotoxicity and must be taken into account to make gene therapy more efficacious.
 
Cite this paper
Rubenstein, M. , Hollowell, C. and Guinan, P. (2015) Following Inhibition of BCL-2 by Antisense Oligonucleotides Compensatory Suppression of Apoptosis Involves the Direct Signal Transduction Pathway of LNCaP Cells. Open Journal of Apoptosis, 4, 1-10. doi: 10.4236/ojapo.2015.41001.
 
References
[1]Rubenstein, M., Tsui, P. and Guinan, P. (2005) Construction of a Bispecific Antisense Oligonucleotide Containing Multiple Binding Sites for the Treatment of Hormone Insensitive Prostate Tumors. Medical Hypotheses, 65, 905-907. http://dx.doi.org/10.1016/j.mehy.2004.12.032
 
[2]Rubenstein, M., Tsui, P. and Guinan, P. (2006) Bispecific Antisense Oligonucleotides with Multiple Binding Sites for the Treatment of Prostate Tumors and Their Applicability to Combination Therapy. Methods and Findings in Experimental and Clinical Pharmacology, 28, 515-518.
http://dx.doi.org/10.1358/mf.2006.28.8.1003571
 
[3]Rubenstein, M., Tsui, P. and Guinan, P. (2007) Combination Chemotherapy Employing Bispecific Antisense Oligonucleotides Having Binding Sites Directed against an Autocrine Regulated Growth Pathway and BCL-2 for the Treatment of Prostate Tumors. Medical Oncology, 24, 372-378.
http://dx.doi.org/10.1007/s12032-007-0023-y
 
[4]Rubenstein, M., Tsui, P. and Guinan, P. (2009) Multigene Targeting of Signal Transduction Pathways for the Treatment of Breast and Prostate Tumors: Comparison between Combination Therapies Employing Bispecific Oligonucleotides with either Rapamycin or Paclitaxel. Medical Oncology, 26, 124-130.
http://dx.doi.org/10.1007/s12032-008-9088-5
 
[5]Rubenstein, M., Tsui, P. and Guinan, P. (2007) Bispecific Antisense Oligonucleotides Having Binding Sites Directed against an Autocrine Regulated Growth Pathway and BCL-2 for the Treatment of Prostate Tumors. Medical Oncology, 24, 189-196. http://dx.doi.org/10.1007/BF02698039
 
[6]Rubenstein, M., Tsui, P. and Guinan, P. (2008) Treatment of MCF-7 Breast Cancer Cells Employing Mono- and Bispecific Antisense Oligonucleotides Having Binding Specificity toward Proteins Associated with Autocrine Regulated Growth and BCL-2. Medical Oncology, 25, 182-186.
http://dx.doi.org/10.1007/s12032-007-9018-y
 
[7]Rubenstein, M., Hollowell, C.M.P. and Guinan, P. (2012) No Compensation in VEGF Expression Follows Antisense Suppression of BCL-2 Activity. In Vivo, 26, 937-940.
 
[8]Yamanaka, K., Miyake, H., Zangemeister-Wittke, U., Jansen, B. and Gleave, M. (2004) Novel Bispecific Antisense Oligonucleotides Inhibiting Both BCL-2 and BCL-xL Expression Induce Apoptosis and Enhance Chemosensitivity in Human Androgen-Independent Prostate Cancer Cells. Proceedings of the American Association for Cancer Research, 45 (online), Abstract #2930.
 
[9]Yip, K.W., Mocanu, J.D., Billie Au, P.Y., Sleep, G.T., Huang, D., Busson, P., Yeh, W.-C., Gilbert, R., O’Sullivan, B., Gullane, P., Bastianutto, C. and Liu, F.F. (2005) Combination BCL-2 Antisense and Radiation Therapy for Nasopharyngeal Cancer. Clinical Cancer Research, 11, 8131-8144.
http://dx.doi.org/10.1158/1078-0432.CCR-05-1266
 
[10]Mu, Z.M., Hachem, P. and Pollack, A. (2005) Antisense BCL-2 Sensitizes Prostate Cancer Cells to Radiation. The Prostate, 65, 331-340. http://dx.doi.org/10.1002/pros.20303
 
[11]Rubenstein, M., Hollowell, C.M.P. and Guinan, P. (2011) In LNCaP Cells Enhanced Expression of the Androgen Receptor Compensates for BCL-2 Suppression by Antisense Oligonucleotides.
Therapeutic Advances in Urology, 3, 51- 57.
 
[12]Rubenstein, M., Anderson, K.M., Tsui, P. and Guinan, P. (2006) Synthesis of Branched Antisense Oligonucleotides Having Multiple Specificities. Treatment of Hormone Insensitive Prostate Cancer. Medical Hypotheses, 67, 1375-1380. http://dx.doi.org/10.1016/j.mehy.2006.05.055
 
[13]Rubenstein, M., Dunea, G. and Guinan, P. (1994) Growth Factor Deprivation Therapy Utilizing Antisense Oligonucleotides. Drug News and Perspectives, 7, 517-524.
 
[14]Rubenstein, M., Mirochnik, Y., Chow, P. and Guinan, P. (1996) Antisense Oligonucleotide Intralesional Therapy of Human PC-3 Prostate Tumors Carried in Athymic Nude Mice. Journal of Surgical Oncology, 62, 194-200. http://dx.doi.org/10.1002/(SICI)1096-9098(199607)62:3<194::AID-JSO9>3.0.CO;2-2             eww150113lx
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