Chairman-Division of Cellular Biology, Hektoen Institute for Medical Research, Chicago, IL 60612, USA; Departments of Biochemistry and Urology, Rush University Medical Center, Chicago, IL 60612, USA; The Division of Urology, Stroger Hospital of Cook County, Chicago, IL 60612, USA.
Ther Adv Urol. 2011 Apr;3(2):51-7. doi: 10.1177/1756287211400493.
Antisense oligonucleotides (oligos) have been employed against in vivo and in vitro prostate cancer models targeting growth stimulatory gene products. While most oligos have targeted growth factors or their receptors, others have been directed against inhibitors of apoptosis. In LNCaP cells we evaluated a set of oligos which targeted and comparably suppressed the expression of the apoptosis inhibitor protein Bcl-2. LNCaP cells adapted to this restoration of apoptosis with a compensatory suppression of caspase-3 expression, a nontargeted promoter of this process. In a continuation of this study we now evaluate the expression of the androgen receptor (AR) following oligo mediated regulation of apoptosis with suppression of Bcl-2.
Monospecific and bispecific oligos directed against Bcl-2 suppressed both the targeted Bcl-2 protein (an inhibitor of apoptosis) and the nontargeted caspase-3 (a promoter of apoptosis), potentially negating the effect on apoptosis produced by specific inhibition of Bcl-2. In contrast, the expression of the AR was significantly enhanced by each type of oligo.
This suggests that when Bcl-2 expression is inhibited there are compensatory changes in the expression of additional proteins which regulate tumor growth, apoptosis and cell survival, and in this scenario might increase or re-establish hormonal sensitivity. If tumors variants are selected which evade gene therapy additional mechanisms of compensation must be identified and subsequently suppressed. These experiments identify pathways by which tumors can develop resistance to gene therapy and suggests additional targets for intervention.
反义寡核苷酸（oligos）已被用于针对前列腺癌的体内和体外模型，以靶向生长刺激基因产物。虽然大多数寡核苷酸针对生长因子或其受体，但其他寡核苷酸则针对凋亡抑制剂。在 LNCaP 细胞中，我们评估了一组针对凋亡抑制剂蛋白 Bcl-2 并可比较地抑制其表达的寡核苷酸。LNCaP 细胞通过 caspase-3 表达的代偿性抑制来适应这种凋亡的恢复，caspase-3 是该过程的非靶向启动子。在这项研究的延续中，我们现在评估了在 Bcl-2 介导的凋亡调节后，雄激素受体（AR）的表达。
针对 Bcl-2 的单特异性和双特异性寡核苷酸均抑制了靶向 Bcl-2 蛋白（凋亡抑制剂）和非靶向 caspase-3（凋亡促进剂），可能否定了对 Bcl-2 特异性抑制产生的凋亡作用。相比之下，每种寡核苷酸都显著增强了 AR 的表达。
这表明，当 Bcl-2 表达被抑制时，会有额外的蛋白质表达发生代偿性变化，这些蛋白质调节肿瘤生长、凋亡和细胞存活，并且在这种情况下可能会增加或重新建立激素敏感性。如果肿瘤变体逃避基因治疗，必须识别并随后抑制其他代偿机制。这些实验确定了肿瘤对基因治疗产生抗性的途径，并提示了其他干预目标。
